Loss of Ezh2 cooperates with Jak2V617F in the development of myelofibrosis in a mouse model of myeloproliferative neoplasm.
Loss of Ezh2 cooperates with Jak2V617F in the development of myelofibrosis in a mouse model of myeloproliferative neoplasm.
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DOI：
10.1182/blood-2015-11-679431
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发表时间：
2016-06
期刊：
影响因子：
20.3
通讯作者：
Yue Yang;H. Akada;Dipmoy Nath;R. Hutchison;G. Mohi
中科院分区：
文献类型：
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作者：
Yue Yang;H. Akada;Dipmoy Nath;R. Hutchison;G. Mohi
在约50%的骨髓纤维化（MF）患者中发现了激活JAK2V617F突变。在MF患者中也观察到组蛋白甲基转移酶增强子zeste同源物2（EZH2）的失活突变。有趣的是，失活EZH2突变通常与MF中的JAK2V617F突变相关，尽管它们在MF发病机制中的作用仍然是难以捉摸的。为了确定EZH2和JAK2V617F突变的伴随损失在造血中的影响，我们产生了EZH2缺陷的Jak2V617F表达小鼠。而Jak2V617F单独表达诱导真性红细胞增多症样疾病，Ezh2的伴随损失显著降低了Jak2V617F敲入小鼠的红细胞和血细胞比容参数，但增加了血小板计数。流式细胞仪分析显示，在Ezh2缺陷的Jak2V617F小鼠红系分化和巨核细胞前体的扩增受损。此外，Ezh2的缺失增强了表达Jak2V617F的造血干细胞的再增殖能力。组织学分析显示Ezh2缺失的Jak2V617F小鼠的骨髓（BM）和脾脏中存在广泛的纤维化。将来自Ezh2缺失的Jak2V617F小鼠的BM移植到野生型动物中导致甚至更快地进展为MF。基因表达谱和染色质免疫沉淀序列分析显示，S100a8，S100a9，Ifi27l2a和Hmga 2的转录去抑制，和H3K27me3在这些基因启动子的水平显着降低Ezh2缺失的造血祖细胞的Jak2V617F小鼠。此外，S100a8、S100a9、Ifi27l2a或Hmga2的过表达显著增加了Jak2V617F小鼠BM中的巨核细胞集落，表明这些Ezh2靶基因在MF中涉及的改变的巨核细胞生成中的作用。总的来说，我们的研究结果表明，Ezh2的丢失与Jak2V617F在表达Jak2V617F的小鼠中MF的发展中合作。
An activating JAK2V617F mutation has been found in ∼50% patients with myelofibrosis (MF). Inactivating mutations in histone methyltransferase enhancer of zeste homolog 2 (EZH2) also have been observed in patients with MF. Interestingly, inactivating EZH2 mutations are often associated with JAK2V617F mutation in MF, although their contributions in the pathogenesis of MF remain elusive. To determine the effects of concomitant loss of EZH2 and JAK2V617F mutation in hematopoiesis, we generated Ezh2-deficient Jak2V617F-expressing mice. Whereas expression of Jak2V617F alone induced a polycythemia vera-like disease, concomitant loss of Ezh2 significantly reduced the red blood cell and hematocrit parameters but increased the platelet counts in Jak2V617F knock-in mice. Flow cytometric analysis showed impairment of erythroid differentiation and expansion of megakaryocytic precursors in Ezh2-deficient Jak2V617F mice. Moreover, loss of Ezh2 enhanced the repopulation capacity of Jak2V617F-expressing hematopoietic stem cells. Histopathologic analysis revealed extensive fibrosis in the bone marrow (BM) and spleen of Ezh2-deleted Jak2V617F mice. Transplantation of BM from Ezh2-deleted Jak2V617F mice into wild-type animals resulted in even faster progression to MF. Gene expression profiling and chromatin immunoprecipitation sequence analysis revealed that S100a8, S100a9, Ifi27l2a, and Hmga2 were transcriptionally derepressed, and the H3K27me3 levels in these gene promoters were significantly reduced on Ezh2 deletion in hematopoietic progenitors of Jak2V617F mice. Furthermore, overexpression of S100a8, S100a9, Ifi27l2a, or Hmga2 significantly increased megakaryocytic colonies in the BM of Jak2V617F mice, indicating a role for these Ezh2 target genes in altered megakaryopoiesis involved in MF. Overall, our results suggest that loss of Ezh2 cooperates with Jak2V617F in the development of MF in Jak2V617F-expressing mice.