Chromatin regulator Asxl1 loss and Nf1 haploinsufficiency cooperate to accelerate myeloid malignancy.
Chromatin regulator Asxl1 loss and Nf1 haploinsufficiency cooperate to accelerate myeloid malignancy.
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染色质调节因子 Asxl1 缺失和 Nf1 单倍体不足共同加速骨髓恶性肿瘤的发生。
DOI：
10.1172/jci121366
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发表时间：
2018
影响因子：
15.9
通讯作者：
Yang Feng Chun
中科院分区：
文献类型：
--
作者：
Zhang Peng;He Fuhong;Bai Jie;Yamamoto Shohei;Chen Shi;Zhang Lin;Sheng Mengyao;Zhang Lei;Guo Ying;Man Na;Yang Hui;Wang Suyun;Cheng Tao;Nimer Stephen D;Zhou Yuan;Xu Mingjiang;Wang Qian Fei;Yang Feng Chun
asxl1在髓系恶性肿瘤中经常发生突变，并且已知与其他基因突变共同发生。然而，与asxl1和协同突变相关的白血病发生的分子机制仍有待阐明。本文中，我们报道asxl1缺失与RAS信号通路负调控因子nf1的单倍不足共同加速了小鼠髓性白血病的发展。造血干细胞和祖细胞中asx11和nf1的缺失导致MYC、NRAS和BRD4等多种通路的功能获得转录激活，这些通路对白血病的发生至关重要。过度活跃的MYC和BRD9转录程序与涉及这些途径的基因启动子区域的H3K4三甲基化升高相关。此外，MAPK通路和BET溴域的药理抑制可阻止白血病的发生并抑制疾病进展inAsxl1Δ/ΔNf1Δ/Δmice。asxl1和RAS通路基因的伴随突变与患者髓系恶性肿瘤的侵袭性进展有关。本研究揭示了表观遗传改变与信号通路的协同作用在加速髓系恶性肿瘤进展中的作用，为治疗asxl1和RAS通路基因突变的髓系恶性肿瘤提供了合理的治疗策略。
ASXL1is frequently mutated in myeloid malignancies and is known to co-occur with other gene mutations. However, the molecular mechanisms underlying the leukemogenesis associated withASXL1and cooperating mutations remain to be elucidated. Here, we report thatAsxl1loss cooperated with haploinsufficiency ofNf1, a negative regulator of the RAS signaling pathway, to accelerate the development of myeloid leukemia in mice. Loss ofAsxl1andNf1in hematopoietic stem and progenitor cells resulted in a gain-of-function transcriptional activation of multiple pathways such as MYC, NRAS, and BRD4 that are critical for leukemogenesis. The hyperactive MYC and BRD9 transcription programs were correlated with elevated H3K4 trimethylation at the promoter regions of genes involving these pathways. Furthermore, pharmacological inhibition of both the MAPK pathway and BET bromodomain prevented leukemia initiation and inhibited disease progression inAsxl1Δ/ΔNf1Δ/Δmice. Concomitant mutations ofASXL1and RAS pathway genes were associated with aggressive progression of myeloid malignancies in patients. This study sheds light on the effect of cooperation between epigenetic alterations and signaling pathways on accelerating the progression of myeloid malignancies and provides a rational therapeutic strategy for the treatment of myeloid malignancies withASXL1and RAS pathway gene mutations.