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Insights into the pathophysiology and therapy of myeloproliferative neoplasms from mouse models

Leukemia Supplements volume 3, pages S27–S28 (2014)Cite this article

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CML (chronic myeloid leukemia) is genetically simple cancer, having a very few point mutations or copy number variations in its early chronic phase genome. Therapies using ABL1 tyrosine kinase inhibitors (TKIs) have dramatically altered the prognosis in CML. The major goal of current molecular research on CML is to understand TKI resistance and disease progression. CML mouse models can provide information and insights into the pathophysiology of this disease that are difficult or impossible to obtain when one is limited to working with human cells. There are two widely used mouse models of CML: binary conditional BCR-ABL1 transgenic mice1, 2 and the retroviral bone marrow transplant (BMT) model of CML.3, 4, 5 In these models, BCR-ABL1-induced CML-like myeloproliferative neoplasm originates from stem/progenitor cells with multi-lineage repopulating activity.5 This neoplasm is transplantable and can progress to blast crisis;5, 6 it is responsive to kinase inhibitors and immunological therapy.7, 8 In this summary, I will focus on three examples where mouse model systems have revealed crucial details about the pathophysiology of CML.

STAT5 is a transcription factor encoded by two closely linked genes in mammals, STAT5a and STAT5b. STAT5 is phosphorylated by JAK family kinases during cytokine and growth factor signaling, and is activated in malignant cells from patients with a wide variety of lymphoid and myeloid malignancies including CML.9 Conditional Stat5 null mutant mice are perinatal lethal due to severe anemia and lung abnormalities,10 and are also characterized by a lack of CD8+ and γ/δ T cells, a profound block in early B-lymphoid development,11 and a normal phenotypic hematopoietic stem cell (HSC) frequency but severe lymphoid and moderate myeloid repopulation defects.12, 13 Upon BM-specific deletion of Stat5a/b using Mx-Cre;Stat5a/bfl/− donor animals, we observed abolishment of detectable BCR-ABL1 leukemia. Notably, however, BCR-ABL1 signaling was maintained in Stat5 null HSC, indicating that these cells were unable to drive the massive expansion of myeloid cells that would have resulted in the development of CML in the absence of STAT5 signaling.14 In serial transplant experiments with BCR-ABL1+Stat5−/− BM cells, recipient animals engrafted and subsequently developed B-cell lymphoblastic leukemia that arose from the transplanted BCR-ABL1+Stat5−/− stem cells. These data suggest that STAT5 is required for the pathogenesis of CML; however, STAT5 deficiency does not eliminate BCR-ABL1+ leukemic stem cells in mice, nor prevent disease progression.

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Acknowledgements

The symposium and publication of this supplement were sponsored by the Division of Hematology/Oncology at the Warren Alpert Medical School of Brown University and NIH Center of Biomedical Research Excellence (COBRE) for Stem Cells Biology at Rhode Island Hospital. RVE was supported by grant from TEVA Pharmaceuticals.

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  1. Hematology/Oncology Division, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, USA

    R A Van Etten

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RVE has received consulting fees from Pfizer Inc. and Acerta Pharma.

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Van Etten, R. Insights into the pathophysiology and therapy of myeloproliferative neoplasms from mouse models. Leukemia Suppl 3 (Suppl 1), S27–S28 (2014). https://doi.org/10.1038/leusup.2014.15

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