Hif1a基因调控JAK2V617F诱导的Ph-型骨髓增殖性肿瘤的分子机制及靶向性治疗策略的研究

The JAK2V617F mutation is found in the majority of myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia and primary myelofibrosis. Similar to chromosome-positive chronic myeloid leukemia, these Philadelphia chromosome-negative (Ph-) MPNs are also derived from hematopoietic stem cells (HSCs) and have a risk of developing thrombosis and acute leukemia. There is still no cure for Ph- MPNs, and we believe that besides targeting JAK2V617F directly, identifying and targeting other key genes that interact with JAK2V617F would be beneficial in treating and delaying disease progression of JAK2V617F-induced MPNs. In this regard, our preliminary studies show that genetic deletion of Hif1a (hypoxia inducible factor 1a) attenuates PV-like MPN and reduces the severity of myelofiborsis in mice. Thus, inhibition of Hif1a function may provide a therapeutic strategy for suppressing JAK2V617F-stimulated abnormal cell proliferation and myelofibrosis. Therefore, we propose to further study the role of Hif1a in PV-like MPN and underlying mechanisms using our mouse disease model and to test the effectiveness of an FDA-approved anti-Hif1a agent in reducing abnormal cell proliferation and myelofibrosis in mice with PV-like MPN and using human PV cells. These studies help to provide a rationale for designing future clinical trials to treat MPN patients by targeting Hif1a.

多数骨髓增殖性肿瘤（myeloproliferative neoplasms, MPNs）中均涉及到JAK2V617F突变，包括真性红细胞增多症(PV)、血小板增多以及骨髓纤维化。与费城染色体阳性急性髓系白血病相类似，这些费城染色体阴性的MPN同样是由造血干细胞分化引起的，并具有诱发血栓形成和急性白血病的风险。Ph- 型MPNs尚无治疗方法，因此除了直接靶向JAK2V617F以外，找到与JAK2V617F相互作用的其它关键基因将有益于治疗和延缓JAK2V617F诱导的MPN的疾病进展。前期研究表明，缺氧诱导因子1a （Hif1a）基因的缺失可以弱化PV样MPN，并减弱小鼠的骨髓纤维化。因此，我们将研究Hif1a在PV样MPN中的作用，并使用已有的小鼠疾病模型的测试抗Hif1a试剂在抑制PV样MPN小鼠及人类PV细胞异常增殖和骨髓纤维化的有效性。

多数骨髓增殖性肿瘤（myeloproliferative neoplasms, MPNs）中均涉及到JAK2V617F突变，包括真性红细胞增多症(PV)、血小板增多以及纤维化。目前尚无有效的根治方法。在本项研究中，我们提出了2个目标：1）研究 Hif1a 基因在JAK2V617F 诱导的细胞异常增殖及骨髓纤维化过程中的作用及机制, 2）验证以Hif1基因为治疗靶点的策略能否有效减弱JAK2V617F 诱导的细胞异常增殖及骨髓纤维化。我们确定了Hif1a 通过Alox5与JAK2V617F诱导的真性红细胞增多症 (polycythemia vera, PV)的功能关系。我们还发现Singulair（一个美国FDA批准用于临床的药物）对JAK2V617F诱发细胞异常增殖有很强的抑制作用。