Inhibition of Histone Deacetylase in Myeloproliferative Neoplasms

描述(申请人提供)：骨髓增生性肿瘤(MPNS)、真性红细胞增多症(PV)、原发性血小板增多症(ET)和原发性骨髓纤维化(PMF)是一组以髓系细胞过度产生为特征的血液系统恶性肿瘤。在大多数PV患者和50-60%的ET和PMF患者中，已经检测到JAK2酪氨酸激酶的体细胞点突变(V617F)。在5-10%的ET和PMF中发现了血小板生成素受体MPL(MPLW515L，MPLW515K)的额外突变。目前，对于这些MPN还没有根治的方法。最近，一些JAK2抑制剂已经被开发出来，并进行了I期临床试验。尽管JAK2抑制剂治疗这些疾病有相当大的热情，但也有一些重要的担忧。有证据表明JAK2V617F阴性的急性髓系白血病经常发生在JAK2V617F阳性的MPN患者中，这增加了JAK2抑制剂治疗可能增加白血病转化风险的可能性。此外，一些接受JAK2抑制剂治疗的患者可能会出现耐药性。因此，确定针对JAK2V617F或MPLW515L或JAK2V617F/MPLW515L下游关键通路的其他治疗方法将有利于MPN的治疗。在初步研究中，我们观察到组蛋白脱乙酰酶(HDAC)抑制剂Vorinostat选择性地抑制JAK2V617F的表达，并诱导表达JAK2V617F或MPLW515L的造血细胞凋亡。我们已经建立了JAK2V617F诱导的MPN的敲入小鼠模型。我们将通过JAK2V617F基因敲入小鼠模型和MPLW515L逆转录病毒骨髓移植模型来检测HDAC抑制剂旋转剂对MPNS的治疗效果。此外，还将探讨MPN中止涡剂抗癌作用的分子机制。这些研究的结果将为使用HDAC抑制剂伏立诺治疗MPNS的I期和II期临床试验奠定基础。 公共卫生相关性：拟议的研究将评估组蛋白脱乙酰酶(HDAC)抑制剂伏立诺在MPNS临床前模型中的疗效，并确定MPNS中伏立恒治疗的生物标记物。这些研究产生的数据将为止涡剂在MPN中的第一阶段和第二阶段临床试验奠定基础。

DESCRIPTION (provided by applicant): The myeloproliferative neoplasmss (MPNs) polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are a group of hematologic malignancies characterized by excessive production of myeloid lineage cells. A somatic point mutation (V617F) in the JAK2 tyrosine kinase has been detected in most patients with PV and 50-60% patients with ET and PMF. Additional mutations in the thrombopoietin receptor MPL (MPLW515L, MPLW515K) have been found in 5-10% cases of ET and PMF. At present, there is no curative therapy for these MPNs. Recently, a number of JAK2 inhibitors have been developed and undergoing Phase I clinical trials. Although there is considerable enthusiasm for JAK2 inhibitor for these disorders, there are also a number of important concerns. There is evidence that JAK2V617F- negative acute myeloid leukemia occurs frequently in patients with a JAK2V617F-positive MPN, raising the possibility that JAK2 inhibitor therapy might increase the risk of leukemic transformation. Moreover, drug resistance is likely to emerge in some patients treated with JAK2 inhibitors. Therefore, identifying additional therapies targeting JAK2V617F or MPLW515L or critical pathways downstream of JAK2V617F/MPLW515L would be beneficial for the treatment of MPNs. In preliminary studies, we have observed that histone deacetylase (HDAC) inhibitor vorinostat selectively inhibits JAK2V617F expression and induces apoptosis in hematopoietic cells expressing JAK2V617F or MPLW515L. We have generated a knock-in mouse model of JAK2V617F-evoked MPN. We will this knock-in mouse model of JAK2V617F and retroviral bone marrow transplant model of MPLW515L to test the efficacy of HDAC inhibitor vorinostat in treating MPNs. The molecular mechanism of anti-cancer activity of vorinostat in MPN will also be determined. The results of these studies will lay the groundwork for Phase I and II clinical trials involving HDAC inhibitor vorinostat in the treatment of MPNs. PUBLIC HEALTH RELEVANCE: The proposed studies will evaluate the efficacy of histone deacetylase (HDAC) inhibitor vorinostat in pre- clinical models of MPNs, and identify the bio-marker for vorinostat therapy in MPNs. The data generated from these studies will lay the groundwork for Phase I and II clinical trials of vorinostat in MPNs.