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Preclinical research suggests chronic myeloid leukemia (CML) patients have a heterogeneous population of long-term hematopoietic stem cells (LTHSCs)—some that can initiate leukemia and some that cannot.
Researchers found they could identify the leukemia-initiating cells by measuring expression of the thrombopoietin receptor MPL. Cells with high MPL expression could initiate CML in mice.
The team said these results suggest the leukemic LTHSCs are the cells responsible for relapse in CML.
“This shows that not all leukemia stem cells are equal,” said study author Ravi Bhatia, MD, of the University of Alabama Birmingham.
“Some are more prone to causing leukemia and relapses, while some others may just hang around without potential for contributing to relapse.”
Dr Bhatia and his colleagues reported these findings in The Journal of Clinical Investigation.
In their experiments, the team used an inducible transgenic mouse model of CML, where the BCR-ABL gene fusion is under the control of a tetracycline-regulated enhancer. This model creates a chronic myeloproliferative disorder that resembles chronic phase CML.
Previous work had shown that only cells with an LTHSC phenotype were capable of long-term repopulation and leukemia-initiating capacity after transplantation to another mouse.
When the researchers transplanted LTHSCs from CML-model mice to other mice, 11 of 20 recipients developed CML, and 9 of 20 showed engraftment with CML cells but did not develop the leukocytosis characteristic of leukemia.
When the LTHSCs from the primary-recipient mice were transferred to secondary recipients, 7 of 17 mice receiving cells from leukemic mice developed CML, and none of the secondary-recipient mice receiving cells from the non-leukemic mice developed CML.
The researchers tested these 2 groups of LTHSCs for differences in gene expression. They found significant differences between the leukemic and non-leukemic LTHSCs for the genes Mpl, c-Myc, CD47, Pten, Sirt1, Ptch1, and Tie2.
The team then decided to focus on Mpl. They used flow cytometry to select LTHSCs with either high or low Mpl expression from CML-model BCR-ABL mice.
Seven of 16 mice receiving Mpl-Hi LTHSCs developed leukemia after transplantation, compared with 1 of 17 receiving Mpl-Lo LTHSCs. This suggested an increased leukemogenic capacity for the Mpl-Hi LTHSCs.
The researchers also investigated the impact of cell-cycle status. They found that CML Mpl-Hi LTHSCs that were in a resting stage of the cell cycle had enhanced long-term engraftment and leukemogenic capacity compared with cycling Mpl-Hi LTHSCs.
The team used virus vectors and shRNA to create Mpl knockdown BCR-ABL LTHSCs and showed that the knockdown cells had a greatly reduced ability to produce leukemia in recipient mice.
The Mpl knockdown cells, after stimulation by the Mpl ligand thrombopoietin, also had reduced expression of the activated transcription factors p-STAT3 and p-STAT5, compared with controls.
Finally, the researchers examined human CML cells for differences between MPL-Hi LTHSCs and MPL-Lo LTHSCs. The results were similar to those observed in mice.
The human MPL-Hi LTHSCs had a higher rate of engraftment than the human MPL-Lo LTHSCs, as tested in a xenograft model using immunodeficient mice.
Additionally, the human MPL-Hi LTHSCs had reduced sensitivity to nilotinib compared with MPL-Lo LTHSCs. However, a Jak/STAT inhibitor significantly reduced cell growth and increased apoptosis in human MPL-Hi LTHSCs.
The researchers concluded that MPL expression is a marker and key regulator of leukemogenic potential and drug sensitivity of CML LTHSCs. They said their findings support further investigation of approaches to antagonize MPL signaling as a potential therapeutic strategy to eliminate leukemia-initiating LTHSCs. 
Image by Difu Wu
Preclinical research suggests chronic myeloid leukemia (CML) patients have a heterogeneous population of long-term hematopoietic stem cells (LTHSCs)—some that can initiate leukemia and some that cannot.
Researchers found they could identify the leukemia-initiating cells by measuring expression of the thrombopoietin receptor MPL. Cells with high MPL expression could initiate CML in mice.
The team said these results suggest the leukemic LTHSCs are the cells responsible for relapse in CML.
“This shows that not all leukemia stem cells are equal,” said study author Ravi Bhatia, MD, of the University of Alabama Birmingham.
“Some are more prone to causing leukemia and relapses, while some others may just hang around without potential for contributing to relapse.”
Dr Bhatia and his colleagues reported these findings in The Journal of Clinical Investigation.
In their experiments, the team used an inducible transgenic mouse model of CML, where the BCR-ABL gene fusion is under the control of a tetracycline-regulated enhancer. This model creates a chronic myeloproliferative disorder that resembles chronic phase CML.
Previous work had shown that only cells with an LTHSC phenotype were capable of long-term repopulation and leukemia-initiating capacity after transplantation to another mouse.
When the researchers transplanted LTHSCs from CML-model mice to other mice, 11 of 20 recipients developed CML, and 9 of 20 showed engraftment with CML cells but did not develop the leukocytosis characteristic of leukemia.
When the LTHSCs from the primary-recipient mice were transferred to secondary recipients, 7 of 17 mice receiving cells from leukemic mice developed CML, and none of the secondary-recipient mice receiving cells from the non-leukemic mice developed CML.
The researchers tested these 2 groups of LTHSCs for differences in gene expression. They found significant differences between the leukemic and non-leukemic LTHSCs for the genes Mpl, c-Myc, CD47, Pten, Sirt1, Ptch1, and Tie2.
The team then decided to focus on Mpl. They used flow cytometry to select LTHSCs with either high or low Mpl expression from CML-model BCR-ABL mice.
Seven of 16 mice receiving Mpl-Hi LTHSCs developed leukemia after transplantation, compared with 1 of 17 receiving Mpl-Lo LTHSCs. This suggested an increased leukemogenic capacity for the Mpl-Hi LTHSCs.
The researchers also investigated the impact of cell-cycle status. They found that CML Mpl-Hi LTHSCs that were in a resting stage of the cell cycle had enhanced long-term engraftment and leukemogenic capacity compared with cycling Mpl-Hi LTHSCs.
The team used virus vectors and shRNA to create Mpl knockdown BCR-ABL LTHSCs and showed that the knockdown cells had a greatly reduced ability to produce leukemia in recipient mice.
The Mpl knockdown cells, after stimulation by the Mpl ligand thrombopoietin, also had reduced expression of the activated transcription factors p-STAT3 and p-STAT5, compared with controls.
Finally, the researchers examined human CML cells for differences between MPL-Hi LTHSCs and MPL-Lo LTHSCs. The results were similar to those observed in mice.
The human MPL-Hi LTHSCs had a higher rate of engraftment than the human MPL-Lo LTHSCs, as tested in a xenograft model using immunodeficient mice.
Additionally, the human MPL-Hi LTHSCs had reduced sensitivity to nilotinib compared with MPL-Lo LTHSCs. However, a Jak/STAT inhibitor significantly reduced cell growth and increased apoptosis in human MPL-Hi LTHSCs.
The researchers concluded that MPL expression is a marker and key regulator of leukemogenic potential and drug sensitivity of CML LTHSCs. They said their findings support further investigation of approaches to antagonize MPL signaling as a potential therapeutic strategy to eliminate leukemia-initiating LTHSCs.
Image by Difu Wu
Preclinical research suggests chronic myeloid leukemia (CML) patients have a heterogeneous population of long-term hematopoietic stem cells (LTHSCs)—some that can initiate leukemia and some that cannot.
Researchers found they could identify the leukemia-initiating cells by measuring expression of the thrombopoietin receptor MPL. Cells with high MPL expression could initiate CML in mice.
The team said these results suggest the leukemic LTHSCs are the cells responsible for relapse in CML.
“This shows that not all leukemia stem cells are equal,” said study author Ravi Bhatia, MD, of the University of Alabama Birmingham.
“Some are more prone to causing leukemia and relapses, while some others may just hang around without potential for contributing to relapse.”
Dr Bhatia and his colleagues reported these findings in The Journal of Clinical Investigation.
In their experiments, the team used an inducible transgenic mouse model of CML, where the BCR-ABL gene fusion is under the control of a tetracycline-regulated enhancer. This model creates a chronic myeloproliferative disorder that resembles chronic phase CML.
Previous work had shown that only cells with an LTHSC phenotype were capable of long-term repopulation and leukemia-initiating capacity after transplantation to another mouse.
When the researchers transplanted LTHSCs from CML-model mice to other mice, 11 of 20 recipients developed CML, and 9 of 20 showed engraftment with CML cells but did not develop the leukocytosis characteristic of leukemia.
When the LTHSCs from the primary-recipient mice were transferred to secondary recipients, 7 of 17 mice receiving cells from leukemic mice developed CML, and none of the secondary-recipient mice receiving cells from the non-leukemic mice developed CML.
The researchers tested these 2 groups of LTHSCs for differences in gene expression. They found significant differences between the leukemic and non-leukemic LTHSCs for the genes Mpl, c-Myc, CD47, Pten, Sirt1, Ptch1, and Tie2.
The team then decided to focus on Mpl. They used flow cytometry to select LTHSCs with either high or low Mpl expression from CML-model BCR-ABL mice.
Seven of 16 mice receiving Mpl-Hi LTHSCs developed leukemia after transplantation, compared with 1 of 17 receiving Mpl-Lo LTHSCs. This suggested an increased leukemogenic capacity for the Mpl-Hi LTHSCs.
The researchers also investigated the impact of cell-cycle status. They found that CML Mpl-Hi LTHSCs that were in a resting stage of the cell cycle had enhanced long-term engraftment and leukemogenic capacity compared with cycling Mpl-Hi LTHSCs.
The team used virus vectors and shRNA to create Mpl knockdown BCR-ABL LTHSCs and showed that the knockdown cells had a greatly reduced ability to produce leukemia in recipient mice.
The Mpl knockdown cells, after stimulation by the Mpl ligand thrombopoietin, also had reduced expression of the activated transcription factors p-STAT3 and p-STAT5, compared with controls.
Finally, the researchers examined human CML cells for differences between MPL-Hi LTHSCs and MPL-Lo LTHSCs. The results were similar to those observed in mice.
The human MPL-Hi LTHSCs had a higher rate of engraftment than the human MPL-Lo LTHSCs, as tested in a xenograft model using immunodeficient mice.
Additionally, the human MPL-Hi LTHSCs had reduced sensitivity to nilotinib compared with MPL-Lo LTHSCs. However, a Jak/STAT inhibitor significantly reduced cell growth and increased apoptosis in human MPL-Hi LTHSCs.
The researchers concluded that MPL expression is a marker and key regulator of leukemogenic potential and drug sensitivity of CML LTHSCs. They said their findings support further investigation of approaches to antagonize MPL signaling as a potential therapeutic strategy to eliminate leukemia-initiating LTHSCs.