Hematology Department, Inserm UMR1170, Gustave Roussy Cancer Campus Grand Paris, Villejuif 94800, France.
Université Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, Paris 94270, France.
Nat Commun. 2017 May 18;8:15429. doi: 10.1038/ncomms15429.
Additional sex combs-like (ASXL) proteins are mammalian homologues of additional sex combs (Asx), a regulator of trithorax and polycomb function in Drosophila. While there has been great interest in ASXL1 due to its frequent mutation in leukemia, little is known about its paralog ASXL2, which is frequently mutated in acute myeloid leukemia patients bearing the RUNX1-RUNX1T1 (AML1-ETO) fusion. Here we report that ASXL2 is required for normal haematopoiesis with distinct, non-overlapping effects from ASXL1 and acts as a haploinsufficient tumour suppressor. While Asxl2 was required for normal haematopoietic stem cell self-renewal, Asxl2 loss promoted AML1-ETO leukemogenesis. Moreover, ASXL2 target genes strongly overlapped with those of RUNX1 and AML1-ETO and ASXL2 loss was associated with increased chromatin accessibility at putative enhancers of key leukemogenic loci. These data reveal that Asxl2 is a critical regulator of haematopoiesis and mediates transcriptional effects that promote leukemogenesis driven by AML1-ETO.
额外的梳状结构（ASXL）蛋白是果蝇中调节转录激活因子和多梳抑制复合物功能的额外梳状结构（Asx）的哺乳动物同源物。虽然由于其在白血病中的频繁突变，人们对 ASXL1 产生了极大的兴趣，但对其同源物 ASXL2 知之甚少，ASXL2 在携带 RUNX1-RUNX1T1（AML1-ETO）融合的急性髓系白血病患者中经常发生突变。在这里，我们报告 ASXL2 是正常造血所必需的，它与 ASXL1 具有不同的、不重叠的作用，并作为一种杂合不足的肿瘤抑制因子发挥作用。虽然 Asxl2 对于正常造血干细胞的自我更新是必需的，但 Asxl2 的缺失促进了 AML1-ETO 白血病的发生。此外，ASXL2 的靶基因与 RUNX1 和 AML1-ETO 的靶基因强烈重叠，ASXL2 的缺失与关键白血病相关基因座的假定增强子的染色质可及性增加有关。这些数据表明，Asxl2 是造血的关键调节因子，并介导促进 AML1-ETO 驱动的白血病发生的转录效应。
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