CD133 marks a stem cell population that drives human primary myelofibrosis
CD133 marks a stem cell population that drives human primary myelofibrosis
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DOI：
10.3324/haematol.2014.118463
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发表时间：
2015-06-01
期刊：
影响因子：
10.1
通讯作者：
Kroeger, Nicolaus
中科院分区：
文献类型：
--
作者：
Triviai, Ioanna;Stuebig, Thomas;Kroeger, Nicolaus
原发性骨髓纤维化是一种骨髓增生性肿瘤，以骨髓纤维化、巨核细胞异型性、髓外造血和向急性髓性白血病转化为特征。迄今为止，在这种疾病的发展过程中，经历时空链事件的干细胞尚未被确定。在这里，我们描述了驱动原发性骨髓纤维化发病机制的CD133（+）干细胞群。患者来源的循环CD133（+）而非CD34(+)CD133（-）细胞具有JAK2（V617F）突变的可变负荷，在体外具有多能克隆能力。CD133（+）细胞在免疫功能低下的小鼠中移植长达10个月，并分化为JAK2-V617F（+）骨髓祖细胞，而不是淋巴祖细胞。我们观察到人类非典型JAK2-V617F（+）巨核细胞的持久性，纤维化前状态的开始，骨髓/脾纤维化和向急性髓系白血病的过渡。白血病细胞起源于含有EZH2（D265H）但缺乏继发性JAK2（V617F）突变的CD133（+）细胞亚群，这与EZH2活性的失调驱动克隆生长并增加急性髓系白血病风险的假设一致。这是患者来源的干细胞群的第一个特征，它驱动类似小鼠原发性骨髓纤维化的慢性和急性阶段的疾病。这些结果揭示了CD133抗原在原发性骨髓纤维化中破译肿瘤克隆的重要性，并为骨髓增殖性肿瘤提供了新的治疗靶点。
Primary myelofibrosis is a myeloproliferative neoplasm characterized by bone marrow fibrosis, megakaryocyte atypia, extramedullary hematopoiesis, and transformation to acute myeloid leukemia. To date the stem cell that undergoes the spatial and temporal chain of events during the development of this disease has not been identified. Here we describe a CD133(+) stem cell population that drives the pathogenesis of primary myelofibrosis. Patient-derived circulating CD133(+) but not CD34(+)CD133(-) cells, with a variable burden for JAK2(V617F) mutation, had multi-potent cloning capacity in vitro. CD133(+) cells engrafted for up to 10 months in immunocompromised mice and differentiated into JAK2-V617F(+) myeloid but not lymphoid progenitors. We observed the persistence of human, atypical JAK2-V617F(+) megakaryocytes, the initiation of a prefibrotic state, bone marrow/splenic fibrosis and transition to acute myeloid leukemia. Leukemic cells arose from a subset of CD133(+) cells harboring EZH2(D265H) but lacking a secondary JAK2(V617F) mutation, consistent with the hypothesis that deregulation of EZH2 activity drives clonal growth and increases the risk of acute myeloid leukemia. This is the first characterization of a patient-derived stem cell population that drives disease resembling both chronic and acute phases of primary myelofibrosis in mice. These results reveal the importance of the CD133 antigen in deciphering the neoplastic clone in primary myelofibrosis and indicate a new therapeutic target for myeloproliferative neoplasms.