User login
Image by Difu Wu
Researchers say they have identified a mechanism governing malignant reprogramming of progenitors into self-renewing leukemia stem cells (LSCs).
And their discovery has revealed a potential new therapeutic approach for chronic myeloid leukemia (CML).
Experiments in mice showed that a targeted monoclonal antibody could impair LSCs’ ability to regenerate and made them easier to eradicate with a tyrosine kinase inhibitor.
Catriona Jamieson, MD, PhD, of the University of California, San Diego, and her colleagues described this research in PNAS.
The researchers found that downregulation of Muscleblind-like 3 (MBNL3) RNA binding proteins resulted in re-expression of a human embryonic stem cell-specific alternative splicing gene regulatory network—a mechanism that controls embryonic stem cell pluripotency and fate. One effect of this was reprogramming of progenitor cells into LSCs in blast crisis CML.
“This is the first description of cancer stem cell generation through decreased expression of a transcriptional repressor of an embryonic pattern of alternative splicing that enhances stem cell self-renewal and survival,” Dr Jamieson said.
“Rather than acquiring multiple DNA mutations, as was previously thought, cancer stem cells in chronic myeloid leukemia switch to embryonic RNA splicing, which enhances their capacity to self-renew or clone themselves.”
“If we can detect and turn off embryonic splicing, we may be able to prevent cancer stem cells from propagating themselves. Also, if we target embryonic versions of proteins that are re-expressed by cancer, like CD44 variant 3, with specific antibodies together with tyrosine kinase inhibitors, we may be able to circumvent cancer relapse—a leading cause of cancer-related mortality.”
The researchers tested this theory in mice. They found that treatment with a humanized pan-CD44 monoclonal antibody and a targeted tyrosine kinase antagonist disrupted the development of LSCs in their protected microenvironment.
This forced the cells to enter the bloodstream, where dasatinib could effectively target them. 
Image by Difu Wu
Researchers say they have identified a mechanism governing malignant reprogramming of progenitors into self-renewing leukemia stem cells (LSCs).
And their discovery has revealed a potential new therapeutic approach for chronic myeloid leukemia (CML).
Experiments in mice showed that a targeted monoclonal antibody could impair LSCs’ ability to regenerate and made them easier to eradicate with a tyrosine kinase inhibitor.
Catriona Jamieson, MD, PhD, of the University of California, San Diego, and her colleagues described this research in PNAS.
The researchers found that downregulation of Muscleblind-like 3 (MBNL3) RNA binding proteins resulted in re-expression of a human embryonic stem cell-specific alternative splicing gene regulatory network—a mechanism that controls embryonic stem cell pluripotency and fate. One effect of this was reprogramming of progenitor cells into LSCs in blast crisis CML.
“This is the first description of cancer stem cell generation through decreased expression of a transcriptional repressor of an embryonic pattern of alternative splicing that enhances stem cell self-renewal and survival,” Dr Jamieson said.
“Rather than acquiring multiple DNA mutations, as was previously thought, cancer stem cells in chronic myeloid leukemia switch to embryonic RNA splicing, which enhances their capacity to self-renew or clone themselves.”
“If we can detect and turn off embryonic splicing, we may be able to prevent cancer stem cells from propagating themselves. Also, if we target embryonic versions of proteins that are re-expressed by cancer, like CD44 variant 3, with specific antibodies together with tyrosine kinase inhibitors, we may be able to circumvent cancer relapse—a leading cause of cancer-related mortality.”
The researchers tested this theory in mice. They found that treatment with a humanized pan-CD44 monoclonal antibody and a targeted tyrosine kinase antagonist disrupted the development of LSCs in their protected microenvironment.
This forced the cells to enter the bloodstream, where dasatinib could effectively target them.
Image by Difu Wu
Researchers say they have identified a mechanism governing malignant reprogramming of progenitors into self-renewing leukemia stem cells (LSCs).
And their discovery has revealed a potential new therapeutic approach for chronic myeloid leukemia (CML).
Experiments in mice showed that a targeted monoclonal antibody could impair LSCs’ ability to regenerate and made them easier to eradicate with a tyrosine kinase inhibitor.
Catriona Jamieson, MD, PhD, of the University of California, San Diego, and her colleagues described this research in PNAS.
The researchers found that downregulation of Muscleblind-like 3 (MBNL3) RNA binding proteins resulted in re-expression of a human embryonic stem cell-specific alternative splicing gene regulatory network—a mechanism that controls embryonic stem cell pluripotency and fate. One effect of this was reprogramming of progenitor cells into LSCs in blast crisis CML.
“This is the first description of cancer stem cell generation through decreased expression of a transcriptional repressor of an embryonic pattern of alternative splicing that enhances stem cell self-renewal and survival,” Dr Jamieson said.
“Rather than acquiring multiple DNA mutations, as was previously thought, cancer stem cells in chronic myeloid leukemia switch to embryonic RNA splicing, which enhances their capacity to self-renew or clone themselves.”
“If we can detect and turn off embryonic splicing, we may be able to prevent cancer stem cells from propagating themselves. Also, if we target embryonic versions of proteins that are re-expressed by cancer, like CD44 variant 3, with specific antibodies together with tyrosine kinase inhibitors, we may be able to circumvent cancer relapse—a leading cause of cancer-related mortality.”
The researchers tested this theory in mice. They found that treatment with a humanized pan-CD44 monoclonal antibody and a targeted tyrosine kinase antagonist disrupted the development of LSCs in their protected microenvironment.
This forced the cells to enter the bloodstream, where dasatinib could effectively target them.