Myeloproliferative disorders (MPDs) are clonal hematologic malignancies characterized by overproduction of one or more myeloid lineage cells. Chromosomal translocations or mutations in protein tyrosine kinases are frequently observed in MPDs. For example, BCR-ABL, the product of Philadelphia chromosome translocation, is associated with chronic myeloid leukemia (CML). Fusion of the Ets family transcription factor TEL to platelet-derived growth factor receptor beta (PDGFR2) results in chronic myelomonocytic leukemia (CMML). A somatic point mutation (V617F) in the Janus Kinase 2 (JAK2) has been found in majority of patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Murine bone marrow transplant and transgenic models of JAK2V617F demonstrate the importance of JAK2 activation in the pathogenesis of MPDs. However, it remains elusive how a single JAK2V617F allele gives rise to three different MPDs- PV, ET and PMF with distinct clinical features. Moreover, the signaling requirement and the precise mechanism for transformation/MPD by JAK2V617F remain largely unknown. In Preliminary Studies, we have developed a novel inducible JAK2V617F knock-in mouse. We will use this inducible knock-in mouse to define the role of JAK2V617F in MPDs. We will examine the effects of JAK2V617F gene dosage (heterozygosity versus homozygosity) on MPD phenotype. We will test if transformation of distinct progenitors results in distinct MPD. We will also assess the potential contribution of genetic background/host modifier on MPD pathogenesis. Using a genetic approach, we will also identify the signaling requirement for JAK2V617F-mediated transformation/MPD. These studies should lead to a better understanding of the role of JAK2V617F in the molecular pathogenesis of myeloproliferative disorders. Moreover, our JAK2V617F knock-in mice will provide a unique and reproducible animal model to test novel therapeutic approaches for JAK2V617F-associated pathologies.
This proposal aims to investigate the role of JAK2V617F mutation in the molecular pathogenesis of MPDs using a novel inducible JAK2V617F knock-in mouse. The proposed studies will provide important new insights into the molecular mechanism of MPDs. The results of these studies may identify new therapeutic targets for MPDs. Moreover, our inducible JAK2V617F knock-in mouse will provide a unique and reproducible animal model to test novel therapies for JAK2V617F-associated MPDs.
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|Yang, Yue; Akada, Hajime; Nath, Dipmoy et al. (2016) Loss of Ezh2 cooperates with Jak2V617F in the development of myelofibrosis in a mouse model of myeloproliferative neoplasm. Blood 127:3410-23|
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|Akada, H; Akada, S; Hutchison, R E et al. (2014) Loss of wild-type Jak2 allele enhances myeloid cell expansion and accelerates myelofibrosis in Jak2V617F knock-in mice. Leukemia 28:1627-35|
|Akada, Hajime; Akada, Saeko; Gajra, Ajeet et al. (2012) Efficacy of vorinostat in a murine model of polycythemia vera. Blood 119:3779-89|
|Yan, Dongqing; Hutchison, Robert E; Mohi, Golam (2012) Critical requirement for Stat5 in a mouse model of polycythemia vera. Blood 119:3539-49|
|Yan, Dongqing; Hutchison, Robert E; Mohi, Golam (2012) Tyrosine 201 is required for constitutive activation of JAK2V617F and efficient induction of myeloproliferative disease in mice. Blood 120:1888-98|
|Akada, Hajime; Akada, Saeko; Hutchison, Robert E et al. (2012) Erythroid lineage-restricted expression of Jak2V617F is sufficient to induce a myeloproliferative disease in mice. Haematologica :|
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