ASXL1/EZH2 mutations promote clonal expansion of neoplastic HSC and impair erythropoiesis in PMF
ASXL1/EZH2 mutations promote clonal expansion of neoplastic HSC and impair erythropoiesis in PMF
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DOI：
10.1038/s41375-018-0159-0
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发表时间：
2018-06
期刊：
影响因子：
11.4
通讯作者：
Ioanna Triviai;Silke Zeschke;Jan Rentel;M. Spanakis;Theo Scherer;R. Gabdoulline;V. Panagiota;F. Thol;M. Heuser;C. Stocking;N. Kröger
中科院分区：
文献类型：
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作者：
Ioanna Triviai;Silke Zeschke;Jan Rentel;M. Spanakis;Theo Scherer;R. Gabdoulline;V. Panagiota;F. Thol;M. Heuser;C. Stocking;N. Kröger
原发性骨髓纤维化(PMF)是一种造血干细胞(HSC)疾病，其特征是所有髓系分化异常，骨髓生态位严重破坏。PMF样本携带几个突变，但它们的细胞来源和层级在调节不同波的克隆性和异常的HSC间隔室的骨髓增殖方面知之甚少。CD133+造血干细胞的>；2000菌落和PMF患者的祖细胞的基因分型证实了肿瘤人群中复杂的遗传异质性。值得注意的是，染色质调节因子ASXL1和/或EZH的突变被确定为第一个遗传损伤，先于JAK2-V617F和CALR突变，因此是PMF亚群中克隆性骨髓生成的驱动因素。具有双重ASXL1/EZH2突变的PMF患者的HSC在免疫缺陷小鼠中的植入率显著高于不存在组蛋白修饰物突变的患者。EZH2突变与PMF患者的异常红细胞生成有关，例如红系祖细胞成熟受损和细胞周期停滞。这些数据强调了组蛋白转录后修饰物在肿瘤干细胞中的重要性，肿瘤干细胞的克隆性生长支持PMF中异常的骨髓生成和白血病前克隆的扩张。
Primary myelofibrosis (PMF) is a hematopoietic stem cell (HSC) disease, characterized by aberrant differentiation of all myeloid lineages and profound disruption of the bone marrow niche. PMF samples carry several mutations, but their cell origin and hierarchy in regulating the different waves of clonal and aberrant myeloproliferation from the prime HSC compartment is poorly understood. Genotyping of >2000 colonies from CD133+HSC and progenitors from PMF patients confirmed the complex genetic heterogeneity within the neoplastic population. Notably, mutations in chromatin regulatorsASXL1and/orEZH2were identified as the first genetic lesions, preceding bothJAK2-V617FandCALRmutations, and are thus drivers of clonal myelopoiesis in a PMF subset. HSC from PMF patients with doubleASXL1/EZH2mutations exhibited significantly higher engraftment in immunodeficient mice than those from patients without histone modifier mutations.EZH2mutations correlate with aberrant erythropoiesis in PMF patients, exemplified by impaired maturation and cell cycle arrest of erythroid progenitors. These data underscore the importance of post-transcriptional modifiers of histones in neoplastic stem cells, whose clonal growth sustains aberrant myelopoiesis and expansion of pre-leukemic clones in PMF.