Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors
Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors
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DOI：
10.1016/j.ccell.2018.01.006
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发表时间：
2018-02-12
期刊：
影响因子：
50.3
通讯作者：
Mead, Adam J.
中科院分区：
文献类型：
--
作者：
Booth, Christopher A. G.;Barkas, Nikolaos;Mead, Adam J.
假定嗜中性粒细胞限制性早期胸腺祖细胞（ETP）是ETP白血病的起源细胞，ETP白血病是一种与EZH 2和RUNX 1失活突变频繁共存以及组成性激活信号通路突变相关的治疗抗性白血病。在小鼠模型中，我们证明了Ezh 2和Runx 1失活靶向早期淋巴祖细胞导致白血病前期ETP显着扩增，显示ETP白血病的转录特征。添加RAS信号传导途径突变（Flt 3-ITD）导致共表达骨髓和淋巴基因的侵袭性白血病，其可以通过扩增的ETP在体内建立和繁殖。小鼠和人ETP白血病在体外和体内均显示出对BET抑制的敏感性，BET抑制可逆转由Ezh 2失活诱导的异常基因表达。
Lympho-myeloid restricted early thymic progenitors (ETPs) are postulated to be the cell of origin for ETP leukemias, a therapy-resistant leukemia associated with frequent co-occurrence of EZH2 and RUNX1 inactivating mutations, and constitutively activating signaling pathway mutations. In a mouse model, we demonstrate that Ezh2 and Runx1 inactivation targeted to early lymphoid progenitors causes a marked expansion of pre-leukemic ETPs, showing transcriptional signatures characteristic of ETP leukemia. Addition of a RAS-signaling pathway mutation (Flt3-ITD) results in an aggressive leukemia co-expressing myeloid and lymphoid genes, which can be established and propagated in vivo by the expanded ETPs. Both mouse and human ETP leukemias show sensitivity to BET inhibition in vitro and in vivo, which reverses aberrant gene expression induced by Ezh2 inactivation.