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Breast cancer drug could treat MPNs, AML
Credit: CDC
Tamoxifen, a drug used to treat breast cancer, may be effective against myeloproliferative neoplasms (MPNs) and acute myeloid leukemia (AML) as well, according to research published in Cell Stem Cell.
The study showed that estrogens regulate the survival, proliferation, and self-renewal of stem cells that give rise to MPNs and AML.
Tamoxifen, which targets estrogen receptors, prevented JAK2V617F-induced MPNs in mice and enhanced the effects of chemotherapy against MLL-AF9-induced AML.
“In this study, we demonstrate that tamoxifen has specific effects on certain cells in the bone marrow: the hematopoietic stem cells and their immediate descendants, known as multipotent progenitors,” explained study author Abel Sánchez-Aguilera, PhD, of Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid.
The researchers found that, unlike in breast cancer, where tamoxifen blocks the action of estrogens, in blood cells, the drug acts by imitating the function of the hormone.
Tamoxifen induced apoptosis in short-term hematopoietic stem cells (HSCs) and multipotent progenitors. But in quiescent, long-term HSCs, the drug prompted proliferation and partial loss of function, which was reversible.
Tamoxifen also prevented polycythemia vera-like MPN from developing in mice with HSCs expressing JAK2V617F. The drug prevented MPN-associated neutrophilia and thrombocytosis; alleviated the early increase in red cell counts, hemoglobin, and hematocrit; decreased bone marrow megakaryocytes; and reduced MPN-associated splenomegaly.
Tamoxifen worked by restoring normal levels of apoptosis in mutant cells. It also prompted apoptosis of human JAK2V617F+ hematopoietic stem and progenitor cells (HSPCs) in a xenograft model.
In these models, tamoxifen caused little alteration in the rest of the blood cells, which were maintained at normal levels even after prolonged treatment with the drug.
“Our results suggest that tamoxifen, at a similar dose used for the treatment of other diseases, might be useful to treat myeloproliferative neoplasms at various stages, without being toxic to normal blood cells,” said study author Simón Méndez-Ferrer, PhD, also of CNIC.
In addition, tamoxifen enhanced the effects of conventional chemotherapy on cancerous cells in mice with MLL-AF9-induced AML.
Tamoxifen- and vehicle-treated mice had similar numbers of MLL-AF9+ cells and HSPCs shortly after chemotherapy. But tamoxifen delayed the reappearance of circulating leukemic cells after chemotherapy.
Tamoxifen-treated mice had fewer leukemic cells in the bone marrow, spleen, and blood, although they ultimately died of their disease.
Nevertheless, the researchers concluded that tamoxifen could be a feasible treatment option for patients with MPNs or AML. And the fact that tamoxifen is already approved for clinical use increases the chances of these results leading to a clinical trial. 
Credit: CDC
Tamoxifen, a drug used to treat breast cancer, may be effective against myeloproliferative neoplasms (MPNs) and acute myeloid leukemia (AML) as well, according to research published in Cell Stem Cell.
The study showed that estrogens regulate the survival, proliferation, and self-renewal of stem cells that give rise to MPNs and AML.
Tamoxifen, which targets estrogen receptors, prevented JAK2V617F-induced MPNs in mice and enhanced the effects of chemotherapy against MLL-AF9-induced AML.
“In this study, we demonstrate that tamoxifen has specific effects on certain cells in the bone marrow: the hematopoietic stem cells and their immediate descendants, known as multipotent progenitors,” explained study author Abel Sánchez-Aguilera, PhD, of Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid.
The researchers found that, unlike in breast cancer, where tamoxifen blocks the action of estrogens, in blood cells, the drug acts by imitating the function of the hormone.
Tamoxifen induced apoptosis in short-term hematopoietic stem cells (HSCs) and multipotent progenitors. But in quiescent, long-term HSCs, the drug prompted proliferation and partial loss of function, which was reversible.
Tamoxifen also prevented polycythemia vera-like MPN from developing in mice with HSCs expressing JAK2V617F. The drug prevented MPN-associated neutrophilia and thrombocytosis; alleviated the early increase in red cell counts, hemoglobin, and hematocrit; decreased bone marrow megakaryocytes; and reduced MPN-associated splenomegaly.
Tamoxifen worked by restoring normal levels of apoptosis in mutant cells. It also prompted apoptosis of human JAK2V617F+ hematopoietic stem and progenitor cells (HSPCs) in a xenograft model.
In these models, tamoxifen caused little alteration in the rest of the blood cells, which were maintained at normal levels even after prolonged treatment with the drug.
“Our results suggest that tamoxifen, at a similar dose used for the treatment of other diseases, might be useful to treat myeloproliferative neoplasms at various stages, without being toxic to normal blood cells,” said study author Simón Méndez-Ferrer, PhD, also of CNIC.
In addition, tamoxifen enhanced the effects of conventional chemotherapy on cancerous cells in mice with MLL-AF9-induced AML.
Tamoxifen- and vehicle-treated mice had similar numbers of MLL-AF9+ cells and HSPCs shortly after chemotherapy. But tamoxifen delayed the reappearance of circulating leukemic cells after chemotherapy.
Tamoxifen-treated mice had fewer leukemic cells in the bone marrow, spleen, and blood, although they ultimately died of their disease.
Nevertheless, the researchers concluded that tamoxifen could be a feasible treatment option for patients with MPNs or AML. And the fact that tamoxifen is already approved for clinical use increases the chances of these results leading to a clinical trial.
Credit: CDC
Tamoxifen, a drug used to treat breast cancer, may be effective against myeloproliferative neoplasms (MPNs) and acute myeloid leukemia (AML) as well, according to research published in Cell Stem Cell.
The study showed that estrogens regulate the survival, proliferation, and self-renewal of stem cells that give rise to MPNs and AML.
Tamoxifen, which targets estrogen receptors, prevented JAK2V617F-induced MPNs in mice and enhanced the effects of chemotherapy against MLL-AF9-induced AML.
“In this study, we demonstrate that tamoxifen has specific effects on certain cells in the bone marrow: the hematopoietic stem cells and their immediate descendants, known as multipotent progenitors,” explained study author Abel Sánchez-Aguilera, PhD, of Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid.
The researchers found that, unlike in breast cancer, where tamoxifen blocks the action of estrogens, in blood cells, the drug acts by imitating the function of the hormone.
Tamoxifen induced apoptosis in short-term hematopoietic stem cells (HSCs) and multipotent progenitors. But in quiescent, long-term HSCs, the drug prompted proliferation and partial loss of function, which was reversible.
Tamoxifen also prevented polycythemia vera-like MPN from developing in mice with HSCs expressing JAK2V617F. The drug prevented MPN-associated neutrophilia and thrombocytosis; alleviated the early increase in red cell counts, hemoglobin, and hematocrit; decreased bone marrow megakaryocytes; and reduced MPN-associated splenomegaly.
Tamoxifen worked by restoring normal levels of apoptosis in mutant cells. It also prompted apoptosis of human JAK2V617F+ hematopoietic stem and progenitor cells (HSPCs) in a xenograft model.
In these models, tamoxifen caused little alteration in the rest of the blood cells, which were maintained at normal levels even after prolonged treatment with the drug.
“Our results suggest that tamoxifen, at a similar dose used for the treatment of other diseases, might be useful to treat myeloproliferative neoplasms at various stages, without being toxic to normal blood cells,” said study author Simón Méndez-Ferrer, PhD, also of CNIC.
In addition, tamoxifen enhanced the effects of conventional chemotherapy on cancerous cells in mice with MLL-AF9-induced AML.
Tamoxifen- and vehicle-treated mice had similar numbers of MLL-AF9+ cells and HSPCs shortly after chemotherapy. But tamoxifen delayed the reappearance of circulating leukemic cells after chemotherapy.
Tamoxifen-treated mice had fewer leukemic cells in the bone marrow, spleen, and blood, although they ultimately died of their disease.
Nevertheless, the researchers concluded that tamoxifen could be a feasible treatment option for patients with MPNs or AML. And the fact that tamoxifen is already approved for clinical use increases the chances of these results leading to a clinical trial.
FDA approves first drug for polycythemia vera
Credit: AFIP
The US Food and Drug Administration (FDA) has expanded the approved use of ruxolitinib (Jakafi) to include treatment of patients with polycythemia vera (PV).
This is the first drug approved by the FDA for this condition.
Ruxolitinib can now be used to treat PV patients who have an inadequate response to hydroxyurea or cannot tolerate the drug.
The FDA said the approval of ruxolitinib for PV patients will help decrease splenomegaly and the need for phlebotomy.
“The approval of Jakafi for polycythemia vera underscores the importance of developing drugs matched to our increasing knowledge of the mechanisms of diseases,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.
“The trial used to evaluate Jakafi confirmed clinically meaningful reductions in spleen size and the need for phlebotomies to control the disease.”
Results from that study, the phase 3 RESPONSE trial, were presented at the 2014 ASCO Annual Meeting. RESPONSE was funded by Incyte Corporation, the company developing ruxolitinib.
The trial included 222 patients who had PV for at least 24 weeks. All patients had an inadequate response to or could not tolerate hydroxyurea, had undergone a phlebotomy procedure, and exhibited an enlarged spleen.
They were randomized to receive ruxolitinib at a starting dose of 10 mg twice daily or best available therapy (BAT) as determined by the investigator on a participant-by-participant basis. The ruxolitinib dose was adjusted as needed throughout the study.
The study was designed to measure the reduced need for phlebotomy beginning at week 8 and continuing through week 32, in addition to at least a 35% reduction in spleen volume at week 32.
Twenty-one percent of ruxolitinib-treated patients met this endpoint, compared to 1% of patients who received BAT. At week 32, 77% of patients on ruxolitinib and 20% on BAT achieved hematocrit control or spleen reduction.
Ruxolitinib was generally well-tolerated, but 3.6% of patients discontinued treatment due to adverse events, compared to 1.8% of patients on BAT.
The most common events associated with ruxolitinib were anemia and thrombocytopenia. The most common non-hematologic events were headache, diarrhea, fatigue, dizziness, constipation, and shingles.
The FDA reviewed ruxolitinib’s use for PV under the agency’s priority review program because, at the time the application was submitted, the drug demonstrated the potential to be a significant improvement over available therapy. Ruxolitinib also received orphan product designation.
Ruxolitinib is currently approved in more than 60 countries for patients with myelofibrosis (MF). In 2011, the FDA approved the drug to treat patients with intermediate or high-risk MF, including primary MF, post-PV MF, and post-essential thrombocythemia MF.
Credit: AFIP
The US Food and Drug Administration (FDA) has expanded the approved use of ruxolitinib (Jakafi) to include treatment of patients with polycythemia vera (PV).
This is the first drug approved by the FDA for this condition.
Ruxolitinib can now be used to treat PV patients who have an inadequate response to hydroxyurea or cannot tolerate the drug.
The FDA said the approval of ruxolitinib for PV patients will help decrease splenomegaly and the need for phlebotomy.
“The approval of Jakafi for polycythemia vera underscores the importance of developing drugs matched to our increasing knowledge of the mechanisms of diseases,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.
“The trial used to evaluate Jakafi confirmed clinically meaningful reductions in spleen size and the need for phlebotomies to control the disease.”
Results from that study, the phase 3 RESPONSE trial, were presented at the 2014 ASCO Annual Meeting. RESPONSE was funded by Incyte Corporation, the company developing ruxolitinib.
The trial included 222 patients who had PV for at least 24 weeks. All patients had an inadequate response to or could not tolerate hydroxyurea, had undergone a phlebotomy procedure, and exhibited an enlarged spleen.
They were randomized to receive ruxolitinib at a starting dose of 10 mg twice daily or best available therapy (BAT) as determined by the investigator on a participant-by-participant basis. The ruxolitinib dose was adjusted as needed throughout the study.
The study was designed to measure the reduced need for phlebotomy beginning at week 8 and continuing through week 32, in addition to at least a 35% reduction in spleen volume at week 32.
Twenty-one percent of ruxolitinib-treated patients met this endpoint, compared to 1% of patients who received BAT. At week 32, 77% of patients on ruxolitinib and 20% on BAT achieved hematocrit control or spleen reduction.
Ruxolitinib was generally well-tolerated, but 3.6% of patients discontinued treatment due to adverse events, compared to 1.8% of patients on BAT.
The most common events associated with ruxolitinib were anemia and thrombocytopenia. The most common non-hematologic events were headache, diarrhea, fatigue, dizziness, constipation, and shingles.
The FDA reviewed ruxolitinib’s use for PV under the agency’s priority review program because, at the time the application was submitted, the drug demonstrated the potential to be a significant improvement over available therapy. Ruxolitinib also received orphan product designation.
Ruxolitinib is currently approved in more than 60 countries for patients with myelofibrosis (MF). In 2011, the FDA approved the drug to treat patients with intermediate or high-risk MF, including primary MF, post-PV MF, and post-essential thrombocythemia MF.
Credit: AFIP
The US Food and Drug Administration (FDA) has expanded the approved use of ruxolitinib (Jakafi) to include treatment of patients with polycythemia vera (PV).
This is the first drug approved by the FDA for this condition.
Ruxolitinib can now be used to treat PV patients who have an inadequate response to hydroxyurea or cannot tolerate the drug.
The FDA said the approval of ruxolitinib for PV patients will help decrease splenomegaly and the need for phlebotomy.
“The approval of Jakafi for polycythemia vera underscores the importance of developing drugs matched to our increasing knowledge of the mechanisms of diseases,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.
“The trial used to evaluate Jakafi confirmed clinically meaningful reductions in spleen size and the need for phlebotomies to control the disease.”
Results from that study, the phase 3 RESPONSE trial, were presented at the 2014 ASCO Annual Meeting. RESPONSE was funded by Incyte Corporation, the company developing ruxolitinib.
The trial included 222 patients who had PV for at least 24 weeks. All patients had an inadequate response to or could not tolerate hydroxyurea, had undergone a phlebotomy procedure, and exhibited an enlarged spleen.
They were randomized to receive ruxolitinib at a starting dose of 10 mg twice daily or best available therapy (BAT) as determined by the investigator on a participant-by-participant basis. The ruxolitinib dose was adjusted as needed throughout the study.
The study was designed to measure the reduced need for phlebotomy beginning at week 8 and continuing through week 32, in addition to at least a 35% reduction in spleen volume at week 32.
Twenty-one percent of ruxolitinib-treated patients met this endpoint, compared to 1% of patients who received BAT. At week 32, 77% of patients on ruxolitinib and 20% on BAT achieved hematocrit control or spleen reduction.
Ruxolitinib was generally well-tolerated, but 3.6% of patients discontinued treatment due to adverse events, compared to 1.8% of patients on BAT.
The most common events associated with ruxolitinib were anemia and thrombocytopenia. The most common non-hematologic events were headache, diarrhea, fatigue, dizziness, constipation, and shingles.
The FDA reviewed ruxolitinib’s use for PV under the agency’s priority review program because, at the time the application was submitted, the drug demonstrated the potential to be a significant improvement over available therapy. Ruxolitinib also received orphan product designation.
Ruxolitinib is currently approved in more than 60 countries for patients with myelofibrosis (MF). In 2011, the FDA approved the drug to treat patients with intermediate or high-risk MF, including primary MF, post-PV MF, and post-essential thrombocythemia MF.
DNA finding has implications for MPNs
Credit: NIGMS
A new study suggests the timing of DNA replication—including where the origin points are and in what order DNA segments are copied—varies from person to person.
The research also revealed the first genetic variants that orchestrate replication timing.
And researchers found evidence suggesting that differences in replication timing may explain why some people are more prone than others to developing myeloproliferative neoplasms (MPNs).
“Everyone’s cells have a plan for copying the genome,” said study author Steven McCarroll, PhD, of Harvard Medical School in Boston. “The idea that we don’t all have the same plan is surprising and interesting.”
Dr McCarroll and his colleagues described this research in Cell.
Replication timing and MPNs
The researchers noted that DNA replication is one of the most fundamental cellular processes, and any variation among people is likely to affect genetic inheritance, including individual disease risk as well as human evolution.
Replication timing is known to affect mutation rates. DNA segments that are copied too late or too early tend to have more errors.
The new study indicates that people with different timing programs therefore have different patterns of mutation risk across their genomes. For example, differences in replication timing could explain predisposition to MPNs.
Researchers previously showed that acquired mutations in JAK2 lead to MPNs. They also noticed that people with JAK2 mutations tend to have a distinctive set of inherited genetic variants nearby, but they weren’t sure how the inherited variants and the new mutations were connected.
Dr McCarroll’s team found that the inherited variants are associated with an “unusually early” replication origin point and proposed that JAK2 is more likely to develop mutations in people with that very early origin point.
“Replication timing may be a way that inherited variation contributes to the risk of later mutations and diseases that we usually think of as arising by chance,” Dr McCarroll said.
A new method of study
Dr McCarroll and his colleagues were able to make these discoveries, in large part, because they invented a new way to obtain DNA replication timing data. They turned to the 1000 Genomes Project, which maintains an online database of sequencing data collected from hundreds of people around the world.
Because much of the DNA in the 1000 Genomes Project had been extracted from actively dividing cells, the team hypothesized that information about replication timing lurked within, and they were right.
They counted the number of copies of individual genes in each genome. Because early replication origins had created more segment copies at the time the sample was taken than late replication origins had, the researchers were able to create a personalized replication timing map for each person.
“People had seen these patterns before but just dismissed them as artifacts of sequencing technology,” Dr McCarroll said. After conducting numerous tests to rule out that possibility, “we found that they reflect real biology.”
The researchers then compared each person’s copy number information with his or her genetic sequence data to see if they could match specific genetic variants to replication timing differences. From 161 samples, the team identified 16 variants. The variants were short, and most were common.
“I think this is the first time we can pinpoint genetic influences on replication timing in any organism,” said study author Amnon Koren, PhD, also of Harvard Medical School.
The variants were located near replication origin points, leading the researchers to wonder if they affect replication timing by altering where a person’s origin points are. The team also suspects the variants work by altering chromatin structure, exposing local sequences to replication machinery.
The group intends to find out. They also want to search for additional variants that control replication timing.
“These 16 variants are almost certainly just the tip of the iceberg,” Dr Koren said.
He and his colleagues believe that, as more variants come to light in future studies, researchers should be better able to manipulate replication timing in the lab and learn more about how it works and its biological significance.
“All you need to do to study replication timing is grow cells and sequence their DNA, which everyone is doing these days,” Dr Koren said. “[This new method] is much easier, faster, and cheaper, and I think it will transform the field because we can now do experiments in large scale.”
“We found that there is biological information in genome sequence data,” Dr McCarroll added. “But this was still an accidental biological experiment. Now imagine the results when we and others actually design experiments to study this phenomenon.”
Credit: NIGMS
A new study suggests the timing of DNA replication—including where the origin points are and in what order DNA segments are copied—varies from person to person.
The research also revealed the first genetic variants that orchestrate replication timing.
And researchers found evidence suggesting that differences in replication timing may explain why some people are more prone than others to developing myeloproliferative neoplasms (MPNs).
“Everyone’s cells have a plan for copying the genome,” said study author Steven McCarroll, PhD, of Harvard Medical School in Boston. “The idea that we don’t all have the same plan is surprising and interesting.”
Dr McCarroll and his colleagues described this research in Cell.
Replication timing and MPNs
The researchers noted that DNA replication is one of the most fundamental cellular processes, and any variation among people is likely to affect genetic inheritance, including individual disease risk as well as human evolution.
Replication timing is known to affect mutation rates. DNA segments that are copied too late or too early tend to have more errors.
The new study indicates that people with different timing programs therefore have different patterns of mutation risk across their genomes. For example, differences in replication timing could explain predisposition to MPNs.
Researchers previously showed that acquired mutations in JAK2 lead to MPNs. They also noticed that people with JAK2 mutations tend to have a distinctive set of inherited genetic variants nearby, but they weren’t sure how the inherited variants and the new mutations were connected.
Dr McCarroll’s team found that the inherited variants are associated with an “unusually early” replication origin point and proposed that JAK2 is more likely to develop mutations in people with that very early origin point.
“Replication timing may be a way that inherited variation contributes to the risk of later mutations and diseases that we usually think of as arising by chance,” Dr McCarroll said.
A new method of study
Dr McCarroll and his colleagues were able to make these discoveries, in large part, because they invented a new way to obtain DNA replication timing data. They turned to the 1000 Genomes Project, which maintains an online database of sequencing data collected from hundreds of people around the world.
Because much of the DNA in the 1000 Genomes Project had been extracted from actively dividing cells, the team hypothesized that information about replication timing lurked within, and they were right.
They counted the number of copies of individual genes in each genome. Because early replication origins had created more segment copies at the time the sample was taken than late replication origins had, the researchers were able to create a personalized replication timing map for each person.
“People had seen these patterns before but just dismissed them as artifacts of sequencing technology,” Dr McCarroll said. After conducting numerous tests to rule out that possibility, “we found that they reflect real biology.”
The researchers then compared each person’s copy number information with his or her genetic sequence data to see if they could match specific genetic variants to replication timing differences. From 161 samples, the team identified 16 variants. The variants were short, and most were common.
“I think this is the first time we can pinpoint genetic influences on replication timing in any organism,” said study author Amnon Koren, PhD, also of Harvard Medical School.
The variants were located near replication origin points, leading the researchers to wonder if they affect replication timing by altering where a person’s origin points are. The team also suspects the variants work by altering chromatin structure, exposing local sequences to replication machinery.
The group intends to find out. They also want to search for additional variants that control replication timing.
“These 16 variants are almost certainly just the tip of the iceberg,” Dr Koren said.
He and his colleagues believe that, as more variants come to light in future studies, researchers should be better able to manipulate replication timing in the lab and learn more about how it works and its biological significance.
“All you need to do to study replication timing is grow cells and sequence their DNA, which everyone is doing these days,” Dr Koren said. “[This new method] is much easier, faster, and cheaper, and I think it will transform the field because we can now do experiments in large scale.”
“We found that there is biological information in genome sequence data,” Dr McCarroll added. “But this was still an accidental biological experiment. Now imagine the results when we and others actually design experiments to study this phenomenon.”
Credit: NIGMS
A new study suggests the timing of DNA replication—including where the origin points are and in what order DNA segments are copied—varies from person to person.
The research also revealed the first genetic variants that orchestrate replication timing.
And researchers found evidence suggesting that differences in replication timing may explain why some people are more prone than others to developing myeloproliferative neoplasms (MPNs).
“Everyone’s cells have a plan for copying the genome,” said study author Steven McCarroll, PhD, of Harvard Medical School in Boston. “The idea that we don’t all have the same plan is surprising and interesting.”
Dr McCarroll and his colleagues described this research in Cell.
Replication timing and MPNs
The researchers noted that DNA replication is one of the most fundamental cellular processes, and any variation among people is likely to affect genetic inheritance, including individual disease risk as well as human evolution.
Replication timing is known to affect mutation rates. DNA segments that are copied too late or too early tend to have more errors.
The new study indicates that people with different timing programs therefore have different patterns of mutation risk across their genomes. For example, differences in replication timing could explain predisposition to MPNs.
Researchers previously showed that acquired mutations in JAK2 lead to MPNs. They also noticed that people with JAK2 mutations tend to have a distinctive set of inherited genetic variants nearby, but they weren’t sure how the inherited variants and the new mutations were connected.
Dr McCarroll’s team found that the inherited variants are associated with an “unusually early” replication origin point and proposed that JAK2 is more likely to develop mutations in people with that very early origin point.
“Replication timing may be a way that inherited variation contributes to the risk of later mutations and diseases that we usually think of as arising by chance,” Dr McCarroll said.
A new method of study
Dr McCarroll and his colleagues were able to make these discoveries, in large part, because they invented a new way to obtain DNA replication timing data. They turned to the 1000 Genomes Project, which maintains an online database of sequencing data collected from hundreds of people around the world.
Because much of the DNA in the 1000 Genomes Project had been extracted from actively dividing cells, the team hypothesized that information about replication timing lurked within, and they were right.
They counted the number of copies of individual genes in each genome. Because early replication origins had created more segment copies at the time the sample was taken than late replication origins had, the researchers were able to create a personalized replication timing map for each person.
“People had seen these patterns before but just dismissed them as artifacts of sequencing technology,” Dr McCarroll said. After conducting numerous tests to rule out that possibility, “we found that they reflect real biology.”
The researchers then compared each person’s copy number information with his or her genetic sequence data to see if they could match specific genetic variants to replication timing differences. From 161 samples, the team identified 16 variants. The variants were short, and most were common.
“I think this is the first time we can pinpoint genetic influences on replication timing in any organism,” said study author Amnon Koren, PhD, also of Harvard Medical School.
The variants were located near replication origin points, leading the researchers to wonder if they affect replication timing by altering where a person’s origin points are. The team also suspects the variants work by altering chromatin structure, exposing local sequences to replication machinery.
The group intends to find out. They also want to search for additional variants that control replication timing.
“These 16 variants are almost certainly just the tip of the iceberg,” Dr Koren said.
He and his colleagues believe that, as more variants come to light in future studies, researchers should be better able to manipulate replication timing in the lab and learn more about how it works and its biological significance.
“All you need to do to study replication timing is grow cells and sequence their DNA, which everyone is doing these days,” Dr Koren said. “[This new method] is much easier, faster, and cheaper, and I think it will transform the field because we can now do experiments in large scale.”
“We found that there is biological information in genome sequence data,” Dr McCarroll added. “But this was still an accidental biological experiment. Now imagine the results when we and others actually design experiments to study this phenomenon.”
Hematology drugs on the fast track
Credit: Bill Branson
The US Food and Drug Administration (FDA) has granted fast track designation to two hematology drugs: the monoclonal antibody MOR208 to treat relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and the antifibrotic agent PRM-151 to treat myelofibrosis (MF).
The FDA’s fast track program aims to expedite the development and review of drugs that have the potential to fill an unmet medical need in serious or life-threatening conditions.
MOR208
MOR208 is a humanized monoclonal antibody targeting CD19. It is under development by MorphoSys AG to treat B-cell malignancies. The program is in phase 2 clinical development in chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and non-Hodgkin lymphoma.
Preclinical research with MOR208 revealed that it can trigger natural killer cell-mediated lysis of ALL cells. The drug had lytic activity against ALL cells from both adult and pediatric patients.
In a phase 1 study, MOR208 exhibited preliminary efficacy in patients with high-risk, heavily pretreated CLL, prompting responses in 67% of patients. Researchers said toxicity was acceptable, but infusion reactions were common.
“First results of our ongoing phase 2 trial, which we will present at this year’s ASH conference in December, have helped to identify diffuse large B-cell lymphoma as a valuable development opportunity for MOR208,” said Arndt Schottelius, chief development officer of MorphoSys AG.
“We are therefore delighted to have received the fast track designation for further development of MOR208 in DLBCL. The more frequent interactions with the FDA that this enables will help us to expedite the development of MOR208 in this particular subset of non-Hodgkin’s lymphoma patients.”
PRM-151
PRM-151 is a recombinant form of an endogenous human protein, pentraxin-2, that is specifically active at the site of tissue damage. PRM-151 is an agonist that acts as a monocyte/macrophage differentiation factor to prevent and potentially reverse fibrosis.
The drug has shown broad anti-fibrotic activity in preclinical models of fibrotic disease, including pulmonary fibrosis, acute and chronic nephropathy, liver fibrosis, and age-related macular degeneration.
PRM-151 has orphan designation in the US for MF and in both the US and European Union for the treatment of idiopathic pulmonary fibrosis.
The FDA’s fast track designation for PRM-151 covers primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF.
“This designation validates our perspective that there is a clear and compelling need for a novel mechanism for the treatment of myelofibrosis that specifically targets the underlying fibrotic processes of the disease,” said Beth Tréhu, MD, FACP, chief medical officer of Promedior Inc., the company developing PRM-151.
“We will continue to work expeditiously to advance this program through the clinic and look forward to presenting the full data set from the first stage of our phase 2 study later this year.”
Preliminary data from the phase 2 study of PRM-151 demonstrated benefits across all clinically relevant measures of MF, including decreases in bone marrow fibrosis, symptom responses, improvements in hemoglobin and platelets, and reductions in spleen size.
The drug also appeared to be well-tolerated and did not prompt myelosuppression.
Credit: Bill Branson
The US Food and Drug Administration (FDA) has granted fast track designation to two hematology drugs: the monoclonal antibody MOR208 to treat relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and the antifibrotic agent PRM-151 to treat myelofibrosis (MF).
The FDA’s fast track program aims to expedite the development and review of drugs that have the potential to fill an unmet medical need in serious or life-threatening conditions.
MOR208
MOR208 is a humanized monoclonal antibody targeting CD19. It is under development by MorphoSys AG to treat B-cell malignancies. The program is in phase 2 clinical development in chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and non-Hodgkin lymphoma.
Preclinical research with MOR208 revealed that it can trigger natural killer cell-mediated lysis of ALL cells. The drug had lytic activity against ALL cells from both adult and pediatric patients.
In a phase 1 study, MOR208 exhibited preliminary efficacy in patients with high-risk, heavily pretreated CLL, prompting responses in 67% of patients. Researchers said toxicity was acceptable, but infusion reactions were common.
“First results of our ongoing phase 2 trial, which we will present at this year’s ASH conference in December, have helped to identify diffuse large B-cell lymphoma as a valuable development opportunity for MOR208,” said Arndt Schottelius, chief development officer of MorphoSys AG.
“We are therefore delighted to have received the fast track designation for further development of MOR208 in DLBCL. The more frequent interactions with the FDA that this enables will help us to expedite the development of MOR208 in this particular subset of non-Hodgkin’s lymphoma patients.”
PRM-151
PRM-151 is a recombinant form of an endogenous human protein, pentraxin-2, that is specifically active at the site of tissue damage. PRM-151 is an agonist that acts as a monocyte/macrophage differentiation factor to prevent and potentially reverse fibrosis.
The drug has shown broad anti-fibrotic activity in preclinical models of fibrotic disease, including pulmonary fibrosis, acute and chronic nephropathy, liver fibrosis, and age-related macular degeneration.
PRM-151 has orphan designation in the US for MF and in both the US and European Union for the treatment of idiopathic pulmonary fibrosis.
The FDA’s fast track designation for PRM-151 covers primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF.
“This designation validates our perspective that there is a clear and compelling need for a novel mechanism for the treatment of myelofibrosis that specifically targets the underlying fibrotic processes of the disease,” said Beth Tréhu, MD, FACP, chief medical officer of Promedior Inc., the company developing PRM-151.
“We will continue to work expeditiously to advance this program through the clinic and look forward to presenting the full data set from the first stage of our phase 2 study later this year.”
Preliminary data from the phase 2 study of PRM-151 demonstrated benefits across all clinically relevant measures of MF, including decreases in bone marrow fibrosis, symptom responses, improvements in hemoglobin and platelets, and reductions in spleen size.
The drug also appeared to be well-tolerated and did not prompt myelosuppression.
Credit: Bill Branson
The US Food and Drug Administration (FDA) has granted fast track designation to two hematology drugs: the monoclonal antibody MOR208 to treat relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and the antifibrotic agent PRM-151 to treat myelofibrosis (MF).
The FDA’s fast track program aims to expedite the development and review of drugs that have the potential to fill an unmet medical need in serious or life-threatening conditions.
MOR208
MOR208 is a humanized monoclonal antibody targeting CD19. It is under development by MorphoSys AG to treat B-cell malignancies. The program is in phase 2 clinical development in chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and non-Hodgkin lymphoma.
Preclinical research with MOR208 revealed that it can trigger natural killer cell-mediated lysis of ALL cells. The drug had lytic activity against ALL cells from both adult and pediatric patients.
In a phase 1 study, MOR208 exhibited preliminary efficacy in patients with high-risk, heavily pretreated CLL, prompting responses in 67% of patients. Researchers said toxicity was acceptable, but infusion reactions were common.
“First results of our ongoing phase 2 trial, which we will present at this year’s ASH conference in December, have helped to identify diffuse large B-cell lymphoma as a valuable development opportunity for MOR208,” said Arndt Schottelius, chief development officer of MorphoSys AG.
“We are therefore delighted to have received the fast track designation for further development of MOR208 in DLBCL. The more frequent interactions with the FDA that this enables will help us to expedite the development of MOR208 in this particular subset of non-Hodgkin’s lymphoma patients.”
PRM-151
PRM-151 is a recombinant form of an endogenous human protein, pentraxin-2, that is specifically active at the site of tissue damage. PRM-151 is an agonist that acts as a monocyte/macrophage differentiation factor to prevent and potentially reverse fibrosis.
The drug has shown broad anti-fibrotic activity in preclinical models of fibrotic disease, including pulmonary fibrosis, acute and chronic nephropathy, liver fibrosis, and age-related macular degeneration.
PRM-151 has orphan designation in the US for MF and in both the US and European Union for the treatment of idiopathic pulmonary fibrosis.
The FDA’s fast track designation for PRM-151 covers primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF.
“This designation validates our perspective that there is a clear and compelling need for a novel mechanism for the treatment of myelofibrosis that specifically targets the underlying fibrotic processes of the disease,” said Beth Tréhu, MD, FACP, chief medical officer of Promedior Inc., the company developing PRM-151.
“We will continue to work expeditiously to advance this program through the clinic and look forward to presenting the full data set from the first stage of our phase 2 study later this year.”
Preliminary data from the phase 2 study of PRM-151 demonstrated benefits across all clinically relevant measures of MF, including decreases in bone marrow fibrosis, symptom responses, improvements in hemoglobin and platelets, and reductions in spleen size.
The drug also appeared to be well-tolerated and did not prompt myelosuppression.
FDA lifts clinical hold on imetelstat
The US Food and Drug Administration (FDA) has removed the full clinical hold placed on the investigational new drug application for the telomerase inhibitor imetelstat.
The hold, which was placed in March, suspended a phase 2 study of imetelstat in patients with essential thrombocythemia (ET) or polycythemia vera (PV), as well as a phase 2 study of the drug in patients with multiple myeloma (MM).
The hold also delayed a planned phase 2 trial in patients with myelofibrosis (MF).
And it temporarily suspended an investigator-sponsored trial of imetelstat in MF. The FDA lifted the hold on the investigator-sponsored trial in June.
The FDA halted these trials due to reports of persistent, low-grade liver function test (LFT) abnormalities observed in the phase 2 study of ET/PV patients and the potential risk of chronic liver injury following long-term exposure to imetelstat. The FDA expressed concern about whether these LFT abnormalities are reversible.
Now, data provided by the Geron Corporation, the company developing imetelstat, has convinced the FDA to lift the hold on all trials.
The FDA said the proposed clinical development plan for imetelstat, which is focused on high-risk myeloid disorders such as MF, is acceptable. Geron Corporation has said it does not intend to conduct further studies with, or develop imetelstat for, patients with ET or PV.
To address the clinical hold, the FDA required Geron to provide follow-up information from imetelstat-treated patients who experienced LFT abnormalities until such abnormalities resolved to normal or baseline.
Geron obtained follow-up information from patients in the previously ongoing company-sponsored phase 2 trials in ET/PV and MM. These data were submitted to the FDA as part of the company’s complete response.
The company’s analysis of these data showed that, in the ET/PV trial, LFT abnormalities resolved to normal or baseline in 14 of 18 follow-up patients. For the remaining 4 patients, at the time of the data cut-off, 3 patients showed improvement in LFT abnormalities, and 1 patient had unresolved LFT abnormalities. Two of the remaining 4 patients continue in follow-up.
In the MM trial, LFT abnormalities resolved to normal or baseline in all 9 follow-up patients. In addition, no emergent hepatic adverse events were reported during follow-up for either study.
The FDA also requested information regarding the reversibility of liver toxicity after chronic imetelstat administration in animals. Geron submitted data from its non-clinical toxicology studies, which included a 6-month study in mice and a 9-month study in cynomolgus monkeys.
In these studies, no clinical pathology changes indicative of hepatocellular injury were observed, and no clear signal of LFT abnormalities were identified.
With the clinical hold lifted, a multicenter phase 2 trial in MF is projected to begin in the first half of 2015.
The US Food and Drug Administration (FDA) has removed the full clinical hold placed on the investigational new drug application for the telomerase inhibitor imetelstat.
The hold, which was placed in March, suspended a phase 2 study of imetelstat in patients with essential thrombocythemia (ET) or polycythemia vera (PV), as well as a phase 2 study of the drug in patients with multiple myeloma (MM).
The hold also delayed a planned phase 2 trial in patients with myelofibrosis (MF).
And it temporarily suspended an investigator-sponsored trial of imetelstat in MF. The FDA lifted the hold on the investigator-sponsored trial in June.
The FDA halted these trials due to reports of persistent, low-grade liver function test (LFT) abnormalities observed in the phase 2 study of ET/PV patients and the potential risk of chronic liver injury following long-term exposure to imetelstat. The FDA expressed concern about whether these LFT abnormalities are reversible.
Now, data provided by the Geron Corporation, the company developing imetelstat, has convinced the FDA to lift the hold on all trials.
The FDA said the proposed clinical development plan for imetelstat, which is focused on high-risk myeloid disorders such as MF, is acceptable. Geron Corporation has said it does not intend to conduct further studies with, or develop imetelstat for, patients with ET or PV.
To address the clinical hold, the FDA required Geron to provide follow-up information from imetelstat-treated patients who experienced LFT abnormalities until such abnormalities resolved to normal or baseline.
Geron obtained follow-up information from patients in the previously ongoing company-sponsored phase 2 trials in ET/PV and MM. These data were submitted to the FDA as part of the company’s complete response.
The company’s analysis of these data showed that, in the ET/PV trial, LFT abnormalities resolved to normal or baseline in 14 of 18 follow-up patients. For the remaining 4 patients, at the time of the data cut-off, 3 patients showed improvement in LFT abnormalities, and 1 patient had unresolved LFT abnormalities. Two of the remaining 4 patients continue in follow-up.
In the MM trial, LFT abnormalities resolved to normal or baseline in all 9 follow-up patients. In addition, no emergent hepatic adverse events were reported during follow-up for either study.
The FDA also requested information regarding the reversibility of liver toxicity after chronic imetelstat administration in animals. Geron submitted data from its non-clinical toxicology studies, which included a 6-month study in mice and a 9-month study in cynomolgus monkeys.
In these studies, no clinical pathology changes indicative of hepatocellular injury were observed, and no clear signal of LFT abnormalities were identified.
With the clinical hold lifted, a multicenter phase 2 trial in MF is projected to begin in the first half of 2015.
The US Food and Drug Administration (FDA) has removed the full clinical hold placed on the investigational new drug application for the telomerase inhibitor imetelstat.
The hold, which was placed in March, suspended a phase 2 study of imetelstat in patients with essential thrombocythemia (ET) or polycythemia vera (PV), as well as a phase 2 study of the drug in patients with multiple myeloma (MM).
The hold also delayed a planned phase 2 trial in patients with myelofibrosis (MF).
And it temporarily suspended an investigator-sponsored trial of imetelstat in MF. The FDA lifted the hold on the investigator-sponsored trial in June.
The FDA halted these trials due to reports of persistent, low-grade liver function test (LFT) abnormalities observed in the phase 2 study of ET/PV patients and the potential risk of chronic liver injury following long-term exposure to imetelstat. The FDA expressed concern about whether these LFT abnormalities are reversible.
Now, data provided by the Geron Corporation, the company developing imetelstat, has convinced the FDA to lift the hold on all trials.
The FDA said the proposed clinical development plan for imetelstat, which is focused on high-risk myeloid disorders such as MF, is acceptable. Geron Corporation has said it does not intend to conduct further studies with, or develop imetelstat for, patients with ET or PV.
To address the clinical hold, the FDA required Geron to provide follow-up information from imetelstat-treated patients who experienced LFT abnormalities until such abnormalities resolved to normal or baseline.
Geron obtained follow-up information from patients in the previously ongoing company-sponsored phase 2 trials in ET/PV and MM. These data were submitted to the FDA as part of the company’s complete response.
The company’s analysis of these data showed that, in the ET/PV trial, LFT abnormalities resolved to normal or baseline in 14 of 18 follow-up patients. For the remaining 4 patients, at the time of the data cut-off, 3 patients showed improvement in LFT abnormalities, and 1 patient had unresolved LFT abnormalities. Two of the remaining 4 patients continue in follow-up.
In the MM trial, LFT abnormalities resolved to normal or baseline in all 9 follow-up patients. In addition, no emergent hepatic adverse events were reported during follow-up for either study.
The FDA also requested information regarding the reversibility of liver toxicity after chronic imetelstat administration in animals. Geron submitted data from its non-clinical toxicology studies, which included a 6-month study in mice and a 9-month study in cynomolgus monkeys.
In these studies, no clinical pathology changes indicative of hepatocellular injury were observed, and no clear signal of LFT abnormalities were identified.
With the clinical hold lifted, a multicenter phase 2 trial in MF is projected to begin in the first half of 2015.
Exome sequencing shows potential as diagnostic tool
Credit: Graham Colm
In a large study, whole-exome sequencing provided 25% of patients with a diagnosis related to a known genetic disease, giving young
patients and their parents some long-sought answers.
The technology was able to detect a number of rare genetic events and new mutations contributing to disease.
Among the medically actionable findings were mutations related to Fanconi anemia, erythrocytosis, hemolytic anemia, and von Willebrand disease.
“The findings in this report, I believe, will forever change the future practice of pediatrics and medicine as a whole,” said study author James R. Lupski, MD, PhD, of the Baylor College of Medicine in Houston.
“It is just a matter of time before genomics moves up on the physician’s list of things to do and is ordered before formulating a differential diagnosis. It will be the new ‘family history’ that, better yet, gets you both the important variants inherited from each parent and the new mutations that contribute to disease susceptibility.”
This research was published in JAMA and is set to be presented on October 21 at the American Society of Human Genetics Annual Meeting in San Diego.
The researchers had previously conducted a pilot study of whole-exome sequencing that included 250 patients and revealed a 25% molecular diagnostic rate.
This current study included 2000 patients (88% pediatric) with clinical whole-exome sequencing analyzed between June 2012 and August 2014. The majority of patients—87.8%—had neurological disorders or a developmental delay, and 12.2% had non-neurological disorders.
The researchers collected peripheral blood, tissue, or extracted DNA samples from patients and their parents. The team sequenced patients’ DNA and compared those results to the normal reference. Any disease-associated mutations were then compared with the parent’s DNA to determine if the child inherited it from one or both parents.
In all, 504 patients (25.2%) received a molecular diagnosis, and 58% of the diagnostic mutations had not previously been reported. Two hundred and eighty patients had a single mutation that caused disease, 181 were autosomal recessive, 65 were X-linked, and 1 was presumed inherited through the mitochondria.
In 5 cases, the patient inherited 2 copies of the mutated gene from the same parent. Of the dominant mutations, 208 were de novo mutations not inherited from either parent, 32 were inherited, and 40 were not determined because parental samples were not available.
Among the de novo mutations, 5 demonstrated mosaicism, which suggested the mutation occurred after fertilization.
The researchers found 708 presumptive causative variant alleles in the 504 cases. Almost 30% of the diagnoses occurred in disease genes only identified by researchers in the last 3 years. In 65 cases, there was no available genetic test other than whole-exome sequencing to find the mutated gene at the time the test was ordered.
Twenty-three patients (about 5%) had mutations in 2 different genes, which could account for various aspects of the patient’s medical condition.
“Doctors generally try to find one diagnosis that explains all the issues a patient may have,” said study author Christine Eng, MD, of the Baylor College of Medicine.
“We have found that, in some cases, a patient may have a blended phenotype of 2 different conditions. That patients may have 2 different rare genetic diseases to explain their condition was an unexpected finding prior to the use of whole-exome sequencing.”
In the 2000 cases, incidental findings of medically actionable results that could result in early diagnosis, screening, or treatment were found in 92 patients. Three patients had more than 1 finding.
“Clinical exome sequencing can assist diagnosis in a wide range of disorders that are diagnostic dilemmas,” Dr Lupski said. “Rare variants and Mendelian disease are important contributors to disease populations. This is in sharp contrast to the thinking of population geneticists, who investigate how common variants contribute to disease susceptibility.”
“We find ‘rare variants’ in aggregate actually contribute to disease susceptibility in a big way. The individual diseases may be rare, but there are thousands of such diseases and many more being defined through genomics.”
Credit: Graham Colm
In a large study, whole-exome sequencing provided 25% of patients with a diagnosis related to a known genetic disease, giving young
patients and their parents some long-sought answers.
The technology was able to detect a number of rare genetic events and new mutations contributing to disease.
Among the medically actionable findings were mutations related to Fanconi anemia, erythrocytosis, hemolytic anemia, and von Willebrand disease.
“The findings in this report, I believe, will forever change the future practice of pediatrics and medicine as a whole,” said study author James R. Lupski, MD, PhD, of the Baylor College of Medicine in Houston.
“It is just a matter of time before genomics moves up on the physician’s list of things to do and is ordered before formulating a differential diagnosis. It will be the new ‘family history’ that, better yet, gets you both the important variants inherited from each parent and the new mutations that contribute to disease susceptibility.”
This research was published in JAMA and is set to be presented on October 21 at the American Society of Human Genetics Annual Meeting in San Diego.
The researchers had previously conducted a pilot study of whole-exome sequencing that included 250 patients and revealed a 25% molecular diagnostic rate.
This current study included 2000 patients (88% pediatric) with clinical whole-exome sequencing analyzed between June 2012 and August 2014. The majority of patients—87.8%—had neurological disorders or a developmental delay, and 12.2% had non-neurological disorders.
The researchers collected peripheral blood, tissue, or extracted DNA samples from patients and their parents. The team sequenced patients’ DNA and compared those results to the normal reference. Any disease-associated mutations were then compared with the parent’s DNA to determine if the child inherited it from one or both parents.
In all, 504 patients (25.2%) received a molecular diagnosis, and 58% of the diagnostic mutations had not previously been reported. Two hundred and eighty patients had a single mutation that caused disease, 181 were autosomal recessive, 65 were X-linked, and 1 was presumed inherited through the mitochondria.
In 5 cases, the patient inherited 2 copies of the mutated gene from the same parent. Of the dominant mutations, 208 were de novo mutations not inherited from either parent, 32 were inherited, and 40 were not determined because parental samples were not available.
Among the de novo mutations, 5 demonstrated mosaicism, which suggested the mutation occurred after fertilization.
The researchers found 708 presumptive causative variant alleles in the 504 cases. Almost 30% of the diagnoses occurred in disease genes only identified by researchers in the last 3 years. In 65 cases, there was no available genetic test other than whole-exome sequencing to find the mutated gene at the time the test was ordered.
Twenty-three patients (about 5%) had mutations in 2 different genes, which could account for various aspects of the patient’s medical condition.
“Doctors generally try to find one diagnosis that explains all the issues a patient may have,” said study author Christine Eng, MD, of the Baylor College of Medicine.
“We have found that, in some cases, a patient may have a blended phenotype of 2 different conditions. That patients may have 2 different rare genetic diseases to explain their condition was an unexpected finding prior to the use of whole-exome sequencing.”
In the 2000 cases, incidental findings of medically actionable results that could result in early diagnosis, screening, or treatment were found in 92 patients. Three patients had more than 1 finding.
“Clinical exome sequencing can assist diagnosis in a wide range of disorders that are diagnostic dilemmas,” Dr Lupski said. “Rare variants and Mendelian disease are important contributors to disease populations. This is in sharp contrast to the thinking of population geneticists, who investigate how common variants contribute to disease susceptibility.”
“We find ‘rare variants’ in aggregate actually contribute to disease susceptibility in a big way. The individual diseases may be rare, but there are thousands of such diseases and many more being defined through genomics.”
Credit: Graham Colm
In a large study, whole-exome sequencing provided 25% of patients with a diagnosis related to a known genetic disease, giving young
patients and their parents some long-sought answers.
The technology was able to detect a number of rare genetic events and new mutations contributing to disease.
Among the medically actionable findings were mutations related to Fanconi anemia, erythrocytosis, hemolytic anemia, and von Willebrand disease.
“The findings in this report, I believe, will forever change the future practice of pediatrics and medicine as a whole,” said study author James R. Lupski, MD, PhD, of the Baylor College of Medicine in Houston.
“It is just a matter of time before genomics moves up on the physician’s list of things to do and is ordered before formulating a differential diagnosis. It will be the new ‘family history’ that, better yet, gets you both the important variants inherited from each parent and the new mutations that contribute to disease susceptibility.”
This research was published in JAMA and is set to be presented on October 21 at the American Society of Human Genetics Annual Meeting in San Diego.
The researchers had previously conducted a pilot study of whole-exome sequencing that included 250 patients and revealed a 25% molecular diagnostic rate.
This current study included 2000 patients (88% pediatric) with clinical whole-exome sequencing analyzed between June 2012 and August 2014. The majority of patients—87.8%—had neurological disorders or a developmental delay, and 12.2% had non-neurological disorders.
The researchers collected peripheral blood, tissue, or extracted DNA samples from patients and their parents. The team sequenced patients’ DNA and compared those results to the normal reference. Any disease-associated mutations were then compared with the parent’s DNA to determine if the child inherited it from one or both parents.
In all, 504 patients (25.2%) received a molecular diagnosis, and 58% of the diagnostic mutations had not previously been reported. Two hundred and eighty patients had a single mutation that caused disease, 181 were autosomal recessive, 65 were X-linked, and 1 was presumed inherited through the mitochondria.
In 5 cases, the patient inherited 2 copies of the mutated gene from the same parent. Of the dominant mutations, 208 were de novo mutations not inherited from either parent, 32 were inherited, and 40 were not determined because parental samples were not available.
Among the de novo mutations, 5 demonstrated mosaicism, which suggested the mutation occurred after fertilization.
The researchers found 708 presumptive causative variant alleles in the 504 cases. Almost 30% of the diagnoses occurred in disease genes only identified by researchers in the last 3 years. In 65 cases, there was no available genetic test other than whole-exome sequencing to find the mutated gene at the time the test was ordered.
Twenty-three patients (about 5%) had mutations in 2 different genes, which could account for various aspects of the patient’s medical condition.
“Doctors generally try to find one diagnosis that explains all the issues a patient may have,” said study author Christine Eng, MD, of the Baylor College of Medicine.
“We have found that, in some cases, a patient may have a blended phenotype of 2 different conditions. That patients may have 2 different rare genetic diseases to explain their condition was an unexpected finding prior to the use of whole-exome sequencing.”
In the 2000 cases, incidental findings of medically actionable results that could result in early diagnosis, screening, or treatment were found in 92 patients. Three patients had more than 1 finding.
“Clinical exome sequencing can assist diagnosis in a wide range of disorders that are diagnostic dilemmas,” Dr Lupski said. “Rare variants and Mendelian disease are important contributors to disease populations. This is in sharp contrast to the thinking of population geneticists, who investigate how common variants contribute to disease susceptibility.”
“We find ‘rare variants’ in aggregate actually contribute to disease susceptibility in a big way. The individual diseases may be rare, but there are thousands of such diseases and many more being defined through genomics.”
A single cell can cause MPNs
Credit: Aaron Logan
Scientists have found that a single cell containing the JAK2-V617F mutation can cause myeloproliferative neoplasms (MPNs) in mice.
The team isolated hematopoietic stem cells (HSCs) from malignant MPNs and transplanted a single cell with mutated JAK2 into groups of healthy mice.
A subset of the mice developed MPNs, which also bore the JAK2 mutation.
The researchers described this work in The Journal of Experimental Medicine.
Pontus Lundberg, PhD, of University Hospital Basel in Switzerland, and his colleagues performed several sets of experiments in which they transplanted JAK2-V617F-expressing cells in dilutions of wild-type bone marrow cells.
In the 1:125 dilution experiment, 24% of mice (4/17) developed polycythemia vera (PV). In the 1:250 dilution experiment, 44% of mice developed either PV or essential thrombocythemia (ET).
The researchers were interested to find that erythrocytosis and thrombocytosis were mutually exclusive in individual mice.
Additional investigation revealed that MPN development did not depend on the acquisition of additional somatic mutations.
To confirm their findings, the researchers then transplanted a single JAK2-V617F-expressing HSC into a total of 113 mice in 4 independent experiments.
Only 1 mouse developed an ET phenotype. Two other mice had transient high chimerism in erythrocytes and/or platelets, but they did not develop ET or PV.
Furthermore, transplanting bone marrow from the mouse with the ET phenotype into secondary recipients did not result in an MPN phenotype.
The researchers also analyzed JAK2-V617F-expressing HSCs in further detail, and they found these HSCs promoted cell division and increased DNA damage.
Higher JAK2-V617F expression was associated with a short-term HSC signature and increased myeloid bias. Lower JAK2-V617F expression was associated with the capacity to stably engraft in secondary recipients.
Dr Lundberg and his colleagues said this research shows that JAK2-V617F has complex effects on HSC biology and that MPNs can develop from a single JAK2-V617F-expressing cell.
Credit: Aaron Logan
Scientists have found that a single cell containing the JAK2-V617F mutation can cause myeloproliferative neoplasms (MPNs) in mice.
The team isolated hematopoietic stem cells (HSCs) from malignant MPNs and transplanted a single cell with mutated JAK2 into groups of healthy mice.
A subset of the mice developed MPNs, which also bore the JAK2 mutation.
The researchers described this work in The Journal of Experimental Medicine.
Pontus Lundberg, PhD, of University Hospital Basel in Switzerland, and his colleagues performed several sets of experiments in which they transplanted JAK2-V617F-expressing cells in dilutions of wild-type bone marrow cells.
In the 1:125 dilution experiment, 24% of mice (4/17) developed polycythemia vera (PV). In the 1:250 dilution experiment, 44% of mice developed either PV or essential thrombocythemia (ET).
The researchers were interested to find that erythrocytosis and thrombocytosis were mutually exclusive in individual mice.
Additional investigation revealed that MPN development did not depend on the acquisition of additional somatic mutations.
To confirm their findings, the researchers then transplanted a single JAK2-V617F-expressing HSC into a total of 113 mice in 4 independent experiments.
Only 1 mouse developed an ET phenotype. Two other mice had transient high chimerism in erythrocytes and/or platelets, but they did not develop ET or PV.
Furthermore, transplanting bone marrow from the mouse with the ET phenotype into secondary recipients did not result in an MPN phenotype.
The researchers also analyzed JAK2-V617F-expressing HSCs in further detail, and they found these HSCs promoted cell division and increased DNA damage.
Higher JAK2-V617F expression was associated with a short-term HSC signature and increased myeloid bias. Lower JAK2-V617F expression was associated with the capacity to stably engraft in secondary recipients.
Dr Lundberg and his colleagues said this research shows that JAK2-V617F has complex effects on HSC biology and that MPNs can develop from a single JAK2-V617F-expressing cell.
Credit: Aaron Logan
Scientists have found that a single cell containing the JAK2-V617F mutation can cause myeloproliferative neoplasms (MPNs) in mice.
The team isolated hematopoietic stem cells (HSCs) from malignant MPNs and transplanted a single cell with mutated JAK2 into groups of healthy mice.
A subset of the mice developed MPNs, which also bore the JAK2 mutation.
The researchers described this work in The Journal of Experimental Medicine.
Pontus Lundberg, PhD, of University Hospital Basel in Switzerland, and his colleagues performed several sets of experiments in which they transplanted JAK2-V617F-expressing cells in dilutions of wild-type bone marrow cells.
In the 1:125 dilution experiment, 24% of mice (4/17) developed polycythemia vera (PV). In the 1:250 dilution experiment, 44% of mice developed either PV or essential thrombocythemia (ET).
The researchers were interested to find that erythrocytosis and thrombocytosis were mutually exclusive in individual mice.
Additional investigation revealed that MPN development did not depend on the acquisition of additional somatic mutations.
To confirm their findings, the researchers then transplanted a single JAK2-V617F-expressing HSC into a total of 113 mice in 4 independent experiments.
Only 1 mouse developed an ET phenotype. Two other mice had transient high chimerism in erythrocytes and/or platelets, but they did not develop ET or PV.
Furthermore, transplanting bone marrow from the mouse with the ET phenotype into secondary recipients did not result in an MPN phenotype.
The researchers also analyzed JAK2-V617F-expressing HSCs in further detail, and they found these HSCs promoted cell division and increased DNA damage.
Higher JAK2-V617F expression was associated with a short-term HSC signature and increased myeloid bias. Lower JAK2-V617F expression was associated with the capacity to stably engraft in secondary recipients.
Dr Lundberg and his colleagues said this research shows that JAK2-V617F has complex effects on HSC biology and that MPNs can develop from a single JAK2-V617F-expressing cell.
Genes aid classification of polycythemia vera
Credit: AFIP
New research has revealed a molecular method for classifying patients with polycythemia vera (PV).
Investigators identified 102 genes that can be used to distinguish patients with aggressive PV from those with indolent disease.
The 2 patient groups exhibited significant differences with regard to leukemic transformation, disease duration, survival, hemoglobin level, thrombosis, splenomegaly, splenectomy, and chemotherapy exposure.
Jerry L. Spivak, MD, of the Johns Hopkins University School of Medicine in Baltimore, and his colleagues conducted this research and recounted the results in NEJM.
The researchers analyzed gene expression in CD34+ cells from 19 patients with PV and compared the results to healthy control subjects of the same sex.
Males with PV had roughly twice as many differentially regulated genes as females with PV—571 and 253, respectively.
The investigators subtracted the genes with sex-specific expression and were left with 102 genes that were differentially regulated (68 upregulated and 34 downregulated) between PV patients and controls.
And the team found they could use these genes to separate patients with indolent PV from those with aggressive disease, as the expression of the genes differed markedly between the 2 groups.
The 2 groups also differed significantly with regard to a number of clinical characteristics. The median disease duration was 14 years for patients with aggressive disease and 6 years for those with indolent disease (P=0.05).
The number of patients who transformed to acute leukemia was 4 and 1, respectively (P=0.04). And the number of patients who were still alive at the time of analysis was 1 and 11, respectively (P=0.001).
There were also significant differences with regard to hemoglobin level (P=0.007), the incidence of thromboembolic events (P=0.04), the frequency of palpable splenomegaly (P=0.03), the rate of splenectomy (P=0.007), and chemotherapy exposure (P=0.03).
However, there were no significant differences between the 2 groups with regard to age, JAK2 V617F neutrophil allele burden, white cell count, or platelet count.
Credit: AFIP
New research has revealed a molecular method for classifying patients with polycythemia vera (PV).
Investigators identified 102 genes that can be used to distinguish patients with aggressive PV from those with indolent disease.
The 2 patient groups exhibited significant differences with regard to leukemic transformation, disease duration, survival, hemoglobin level, thrombosis, splenomegaly, splenectomy, and chemotherapy exposure.
Jerry L. Spivak, MD, of the Johns Hopkins University School of Medicine in Baltimore, and his colleagues conducted this research and recounted the results in NEJM.
The researchers analyzed gene expression in CD34+ cells from 19 patients with PV and compared the results to healthy control subjects of the same sex.
Males with PV had roughly twice as many differentially regulated genes as females with PV—571 and 253, respectively.
The investigators subtracted the genes with sex-specific expression and were left with 102 genes that were differentially regulated (68 upregulated and 34 downregulated) between PV patients and controls.
And the team found they could use these genes to separate patients with indolent PV from those with aggressive disease, as the expression of the genes differed markedly between the 2 groups.
The 2 groups also differed significantly with regard to a number of clinical characteristics. The median disease duration was 14 years for patients with aggressive disease and 6 years for those with indolent disease (P=0.05).
The number of patients who transformed to acute leukemia was 4 and 1, respectively (P=0.04). And the number of patients who were still alive at the time of analysis was 1 and 11, respectively (P=0.001).
There were also significant differences with regard to hemoglobin level (P=0.007), the incidence of thromboembolic events (P=0.04), the frequency of palpable splenomegaly (P=0.03), the rate of splenectomy (P=0.007), and chemotherapy exposure (P=0.03).
However, there were no significant differences between the 2 groups with regard to age, JAK2 V617F neutrophil allele burden, white cell count, or platelet count.
Credit: AFIP
New research has revealed a molecular method for classifying patients with polycythemia vera (PV).
Investigators identified 102 genes that can be used to distinguish patients with aggressive PV from those with indolent disease.
The 2 patient groups exhibited significant differences with regard to leukemic transformation, disease duration, survival, hemoglobin level, thrombosis, splenomegaly, splenectomy, and chemotherapy exposure.
Jerry L. Spivak, MD, of the Johns Hopkins University School of Medicine in Baltimore, and his colleagues conducted this research and recounted the results in NEJM.
The researchers analyzed gene expression in CD34+ cells from 19 patients with PV and compared the results to healthy control subjects of the same sex.
Males with PV had roughly twice as many differentially regulated genes as females with PV—571 and 253, respectively.
The investigators subtracted the genes with sex-specific expression and were left with 102 genes that were differentially regulated (68 upregulated and 34 downregulated) between PV patients and controls.
And the team found they could use these genes to separate patients with indolent PV from those with aggressive disease, as the expression of the genes differed markedly between the 2 groups.
The 2 groups also differed significantly with regard to a number of clinical characteristics. The median disease duration was 14 years for patients with aggressive disease and 6 years for those with indolent disease (P=0.05).
The number of patients who transformed to acute leukemia was 4 and 1, respectively (P=0.04). And the number of patients who were still alive at the time of analysis was 1 and 11, respectively (P=0.001).
There were also significant differences with regard to hemoglobin level (P=0.007), the incidence of thromboembolic events (P=0.04), the frequency of palpable splenomegaly (P=0.03), the rate of splenectomy (P=0.007), and chemotherapy exposure (P=0.03).
However, there were no significant differences between the 2 groups with regard to age, JAK2 V617F neutrophil allele burden, white cell count, or platelet count.
Drug gets fast track designation for MF
Credit: Peter Anderson
The US Food and Drug Administration (FDA) is expediting its review of pacritinib, a tyrosine kinase inhibitor with activity against JAK2 and FLT3, by granting the drug fast track designation.
Pacritinib is under review as a treatment for patients with intermediate- and high-risk myelofibrosis (MF), including those with disease-related or treatment-induced thrombocytopenia and those who cannot tolerate or do not respond well to other JAK2 therapy.
The FDA’s fast track process is designed to expedite the review of drugs to treat serious conditions and fill an unmet medical need.
The program enables a company—in this case, CTI BioPharma—to submit sections of a new drug application on a rolling basis as data becomes available.
That way, the FDA can review sections of the application as they are received, rather than waiting until every section of the application is completed before the entire application can be reviewed. This often leads to faster approval.
Pacritinib is currently under investigation in two phase 3 clinical trials, known as the PERSIST program, for patients with MF.
One of these trials, known as PERSIST-1, includes a broad set of patients without limitations on platelet counts. The other, PERSIST-2, includes patients with low platelet counts.
PERSIST-1
In July 2014, CTI Biopharma completed enrollment in the PERSIST-1 trial, which was designed to enroll approximately 320 patients.
This randomized trial was designed to compared the efficacy and safety of pacritinib with that of best available therapy, other than JAK inhibitors, in patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, without exclusion for low platelet counts.
The primary endpoint is the percentage of patients achieving at least a 35% reduction in spleen volume, measured by MRI or CT from baseline to 24 weeks of treatment.
PERSIST-2
In March 2014, CTI announced the initiation of the PERSIST-2 trial, a comparison of pacritinib and best available therapy, including approved JAK2 inhibitors that are dosed according to product label, in patients with MF whose platelet counts are 100,000/uL or lower.
The trial is designed to enroll up to 300 patients in North America, Europe, Australia, and New Zealand. In October 2013, CTI reached agreement with the FDA on a special protocol assessment for the trial, a written agreement between CTI and the FDA regarding the planned design, endpoints, and statistical analysis approach of the trial to be used in support of a potential new drug application.
Under the special protocol assessment, the trial will have two primary endpoints. The first is the percentage of patients achieving a 35% or greater reduction in spleen volume, measured by MRI or CT scan from baseline to 24 weeks of treatment.
The second primary endpoint is the percentage of patients achieving a total symptom score reduction of 50% or greater using 6 key symptoms, as measured by the modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0) diary from baseline to 24 weeks.
More details on the PERSIST-1 and PERSIST-2 trials can be found at www.clinicaltrials.gov.
Credit: Peter Anderson
The US Food and Drug Administration (FDA) is expediting its review of pacritinib, a tyrosine kinase inhibitor with activity against JAK2 and FLT3, by granting the drug fast track designation.
Pacritinib is under review as a treatment for patients with intermediate- and high-risk myelofibrosis (MF), including those with disease-related or treatment-induced thrombocytopenia and those who cannot tolerate or do not respond well to other JAK2 therapy.
The FDA’s fast track process is designed to expedite the review of drugs to treat serious conditions and fill an unmet medical need.
The program enables a company—in this case, CTI BioPharma—to submit sections of a new drug application on a rolling basis as data becomes available.
That way, the FDA can review sections of the application as they are received, rather than waiting until every section of the application is completed before the entire application can be reviewed. This often leads to faster approval.
Pacritinib is currently under investigation in two phase 3 clinical trials, known as the PERSIST program, for patients with MF.
One of these trials, known as PERSIST-1, includes a broad set of patients without limitations on platelet counts. The other, PERSIST-2, includes patients with low platelet counts.
PERSIST-1
In July 2014, CTI Biopharma completed enrollment in the PERSIST-1 trial, which was designed to enroll approximately 320 patients.
This randomized trial was designed to compared the efficacy and safety of pacritinib with that of best available therapy, other than JAK inhibitors, in patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, without exclusion for low platelet counts.
The primary endpoint is the percentage of patients achieving at least a 35% reduction in spleen volume, measured by MRI or CT from baseline to 24 weeks of treatment.
PERSIST-2
In March 2014, CTI announced the initiation of the PERSIST-2 trial, a comparison of pacritinib and best available therapy, including approved JAK2 inhibitors that are dosed according to product label, in patients with MF whose platelet counts are 100,000/uL or lower.
The trial is designed to enroll up to 300 patients in North America, Europe, Australia, and New Zealand. In October 2013, CTI reached agreement with the FDA on a special protocol assessment for the trial, a written agreement between CTI and the FDA regarding the planned design, endpoints, and statistical analysis approach of the trial to be used in support of a potential new drug application.
Under the special protocol assessment, the trial will have two primary endpoints. The first is the percentage of patients achieving a 35% or greater reduction in spleen volume, measured by MRI or CT scan from baseline to 24 weeks of treatment.
The second primary endpoint is the percentage of patients achieving a total symptom score reduction of 50% or greater using 6 key symptoms, as measured by the modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0) diary from baseline to 24 weeks.
More details on the PERSIST-1 and PERSIST-2 trials can be found at www.clinicaltrials.gov.
Credit: Peter Anderson
The US Food and Drug Administration (FDA) is expediting its review of pacritinib, a tyrosine kinase inhibitor with activity against JAK2 and FLT3, by granting the drug fast track designation.
Pacritinib is under review as a treatment for patients with intermediate- and high-risk myelofibrosis (MF), including those with disease-related or treatment-induced thrombocytopenia and those who cannot tolerate or do not respond well to other JAK2 therapy.
The FDA’s fast track process is designed to expedite the review of drugs to treat serious conditions and fill an unmet medical need.
The program enables a company—in this case, CTI BioPharma—to submit sections of a new drug application on a rolling basis as data becomes available.
That way, the FDA can review sections of the application as they are received, rather than waiting until every section of the application is completed before the entire application can be reviewed. This often leads to faster approval.
Pacritinib is currently under investigation in two phase 3 clinical trials, known as the PERSIST program, for patients with MF.
One of these trials, known as PERSIST-1, includes a broad set of patients without limitations on platelet counts. The other, PERSIST-2, includes patients with low platelet counts.
PERSIST-1
In July 2014, CTI Biopharma completed enrollment in the PERSIST-1 trial, which was designed to enroll approximately 320 patients.
This randomized trial was designed to compared the efficacy and safety of pacritinib with that of best available therapy, other than JAK inhibitors, in patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, without exclusion for low platelet counts.
The primary endpoint is the percentage of patients achieving at least a 35% reduction in spleen volume, measured by MRI or CT from baseline to 24 weeks of treatment.
PERSIST-2
In March 2014, CTI announced the initiation of the PERSIST-2 trial, a comparison of pacritinib and best available therapy, including approved JAK2 inhibitors that are dosed according to product label, in patients with MF whose platelet counts are 100,000/uL or lower.
The trial is designed to enroll up to 300 patients in North America, Europe, Australia, and New Zealand. In October 2013, CTI reached agreement with the FDA on a special protocol assessment for the trial, a written agreement between CTI and the FDA regarding the planned design, endpoints, and statistical analysis approach of the trial to be used in support of a potential new drug application.
Under the special protocol assessment, the trial will have two primary endpoints. The first is the percentage of patients achieving a 35% or greater reduction in spleen volume, measured by MRI or CT scan from baseline to 24 weeks of treatment.
The second primary endpoint is the percentage of patients achieving a total symptom score reduction of 50% or greater using 6 key symptoms, as measured by the modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0) diary from baseline to 24 weeks.
More details on the PERSIST-1 and PERSIST-2 trials can be found at www.clinicaltrials.gov.
Biochemical cascade can lead to MPNs
Credit: Indiana University
Preclinical research has revealed a cascade of molecular events in the bone marrow that produce high levels of inflammation, disrupt hematopoiesis, and lead to the development of myeloproliferative neoplasms (MPNs).
The discovery points the way to potential new strategies for treating MPNs and leukemias and further illuminates the relationship between inflammation and cancer, according to Nadia Carlesso, MD, PhD, of the Indiana University School of Medicine in Indianapolis.
Dr Carlesso and her colleagues described the discovery in Cell Stem Cell.
The team used a mouse model to elucidate the role of Notch in hematopoiesis. And they found that loss of Notch function in the microenvironment causes a chain of molecular events that result in excess production of inflammatory factors.
“Some of these inflammatory molecules are cytokines that induce uncontrolled proliferation of myeloid cells and lead to myeloproliferative disorders,” Dr Carlesso said. “[However,] loss of Notch has to occur in specific cells of the bone marrow microenvironment, like endothelial cells, to really be capable to trigger such a high inflammatory status.”
Specifically, Dr Carlesso and her colleagues showed that Notch signaling represses expression of the microRNA miR-155 by promoting binding of RBPJ, a nonredundant downstream effector of the canonical Notch signaling cascade, to the miR-155 promoter.
Loss of Notch/RBPJ signaling upregulates miR-155 in bone marrow endothelial cells. And this leads to miR-155-mediated targeting of the NF-kB inhibitor kB-Ras1, NF-kB activation, increased proinflammatory cytokine production, and the development of an MPN-like disorder.
But when the researchers deleted miR-155 in the stroma of RBPJ_/_ mice, they were able to prevent cytokine induction and the MPN-like disease.
The team also discovered elevated levels of miR-155 in samples from humans with MPNs. This suggests that developing drugs to target the inflammatory reaction at key points could be a promising strategy to limit the development of MPNs in humans.
Dr Carlesso noted that a key finding of this research was that the molecular cascade leading to inflammation was not occurring directly in hematopoietic stem cells but in cells of the bone marrow microenvironment.
“This work indicates that we need to target not only the tumor cells but also the inflammatory microenvironment that surrounds them and may contribute to their generation,” she said. “We believe that this combined strategy will be more effective in preventing myeloproliferative disease progression and transformation in acute leukemias.”
Dr Carlesso also pointed out that, because Notch is an oncogene, it is often targeted by therapies for other types of cancer. But this research suggests targeting Notch can have adverse effects on hematopoiesis, and clinicians should be aware of this risk.
Credit: Indiana University
Preclinical research has revealed a cascade of molecular events in the bone marrow that produce high levels of inflammation, disrupt hematopoiesis, and lead to the development of myeloproliferative neoplasms (MPNs).
The discovery points the way to potential new strategies for treating MPNs and leukemias and further illuminates the relationship between inflammation and cancer, according to Nadia Carlesso, MD, PhD, of the Indiana University School of Medicine in Indianapolis.
Dr Carlesso and her colleagues described the discovery in Cell Stem Cell.
The team used a mouse model to elucidate the role of Notch in hematopoiesis. And they found that loss of Notch function in the microenvironment causes a chain of molecular events that result in excess production of inflammatory factors.
“Some of these inflammatory molecules are cytokines that induce uncontrolled proliferation of myeloid cells and lead to myeloproliferative disorders,” Dr Carlesso said. “[However,] loss of Notch has to occur in specific cells of the bone marrow microenvironment, like endothelial cells, to really be capable to trigger such a high inflammatory status.”
Specifically, Dr Carlesso and her colleagues showed that Notch signaling represses expression of the microRNA miR-155 by promoting binding of RBPJ, a nonredundant downstream effector of the canonical Notch signaling cascade, to the miR-155 promoter.
Loss of Notch/RBPJ signaling upregulates miR-155 in bone marrow endothelial cells. And this leads to miR-155-mediated targeting of the NF-kB inhibitor kB-Ras1, NF-kB activation, increased proinflammatory cytokine production, and the development of an MPN-like disorder.
But when the researchers deleted miR-155 in the stroma of RBPJ_/_ mice, they were able to prevent cytokine induction and the MPN-like disease.
The team also discovered elevated levels of miR-155 in samples from humans with MPNs. This suggests that developing drugs to target the inflammatory reaction at key points could be a promising strategy to limit the development of MPNs in humans.
Dr Carlesso noted that a key finding of this research was that the molecular cascade leading to inflammation was not occurring directly in hematopoietic stem cells but in cells of the bone marrow microenvironment.
“This work indicates that we need to target not only the tumor cells but also the inflammatory microenvironment that surrounds them and may contribute to their generation,” she said. “We believe that this combined strategy will be more effective in preventing myeloproliferative disease progression and transformation in acute leukemias.”
Dr Carlesso also pointed out that, because Notch is an oncogene, it is often targeted by therapies for other types of cancer. But this research suggests targeting Notch can have adverse effects on hematopoiesis, and clinicians should be aware of this risk.
Credit: Indiana University
Preclinical research has revealed a cascade of molecular events in the bone marrow that produce high levels of inflammation, disrupt hematopoiesis, and lead to the development of myeloproliferative neoplasms (MPNs).
The discovery points the way to potential new strategies for treating MPNs and leukemias and further illuminates the relationship between inflammation and cancer, according to Nadia Carlesso, MD, PhD, of the Indiana University School of Medicine in Indianapolis.
Dr Carlesso and her colleagues described the discovery in Cell Stem Cell.
The team used a mouse model to elucidate the role of Notch in hematopoiesis. And they found that loss of Notch function in the microenvironment causes a chain of molecular events that result in excess production of inflammatory factors.
“Some of these inflammatory molecules are cytokines that induce uncontrolled proliferation of myeloid cells and lead to myeloproliferative disorders,” Dr Carlesso said. “[However,] loss of Notch has to occur in specific cells of the bone marrow microenvironment, like endothelial cells, to really be capable to trigger such a high inflammatory status.”
Specifically, Dr Carlesso and her colleagues showed that Notch signaling represses expression of the microRNA miR-155 by promoting binding of RBPJ, a nonredundant downstream effector of the canonical Notch signaling cascade, to the miR-155 promoter.
Loss of Notch/RBPJ signaling upregulates miR-155 in bone marrow endothelial cells. And this leads to miR-155-mediated targeting of the NF-kB inhibitor kB-Ras1, NF-kB activation, increased proinflammatory cytokine production, and the development of an MPN-like disorder.
But when the researchers deleted miR-155 in the stroma of RBPJ_/_ mice, they were able to prevent cytokine induction and the MPN-like disease.
The team also discovered elevated levels of miR-155 in samples from humans with MPNs. This suggests that developing drugs to target the inflammatory reaction at key points could be a promising strategy to limit the development of MPNs in humans.
Dr Carlesso noted that a key finding of this research was that the molecular cascade leading to inflammation was not occurring directly in hematopoietic stem cells but in cells of the bone marrow microenvironment.
“This work indicates that we need to target not only the tumor cells but also the inflammatory microenvironment that surrounds them and may contribute to their generation,” she said. “We believe that this combined strategy will be more effective in preventing myeloproliferative disease progression and transformation in acute leukemias.”
Dr Carlesso also pointed out that, because Notch is an oncogene, it is often targeted by therapies for other types of cancer. But this research suggests targeting Notch can have adverse effects on hematopoiesis, and clinicians should be aware of this risk.