Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification
Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification
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DOI：
10.1038/s41375-018-0198-6
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发表时间：
2018-07
期刊：
影响因子：
11.4
通讯作者：
M. Uni;Yosuke Masamoto;Tomohiko Sato;Yasuhiko Kamikubo;S. Arai;E. Hara;M. Kurokawa
中科院分区：
文献类型：
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作者：
M. Uni;Yosuke Masamoto;Tomohiko Sato;Yasuhiko Kamikubo;S. Arai;E. Hara;M. Kurokawa
尽管具有独特的临床重要性，但额外性梳状 1 (ASXL1) 突变如何促进癌前病变发病机制的分子机制在很大程度上尚不清楚。在这里，我们用新产生的敲入小鼠研究了突变体的生物学效应。Asxl1G643f杂合子（Asxl1G643fs/+）小鼠出现了重现人类低危骨髓增生异常综合征（MDS）的表型，其中一些在长时间潜伏后出现了MDS/骨髓增生性肿瘤样疾病。在 Asxl1G643fs/+ 造血干细胞 (HSC) 中，p16Ink4 启动子区域周围的 H2AK119ub1 水平显着降低，表明突变的 Asxl1 扰乱了 Bmi1 驱动的 H2AK119ub1 组蛋白修饰。与野生型 ASXL1 蛋白不同，ASXL1 突变体无法与 BMI1 相互作用。从 Asxl1G643fs/+ p16Ink4a 杂合小鼠中获得了 HSC 库的恢复和造血干细胞和祖细胞凋亡增加的改善。这些结果表明，Asxl1 突变体和 Bmi1 之间蛋白质相互作用的丧失影响了 PRC1 的活性，随后异常组蛋白泛素化对 p16Ink4a 的去抑制可诱导细胞衰老，导致 Asxl1G643fs/+ 小鼠出现低风险 MDS 样表型。该模型提供了一个有用的平台来揭示 ASXL1 突变引起的血液疾病的分子基础，并为这些患者制定治疗策略。
In spite of distinct clinical importance, the molecular mechanisms how Additional sex combs-like 1 (ASXL1) mutation contributes to the pathogenesis of premalignant conditions are largely unknown. Here, with newly generated knock-in mice, we investigated the biological effects of the mutant.Asxl1G643fsheterozygous (Asxl1G643fs/+) mice developed phenotypes recapitulating human low-risk myelodysplastic syndromes (MDS), and some of them developed MDS/myeloproliferative neoplasm-like disease after long latency. H2AK119ub1 level around the promoter region ofp16Ink4awas significantly decreased inAsxl1G643fs/+hematopoietic stem cells (HSC), suggesting perturbation of Bmi1-driven H2AK119ub1 histone modification by mutated Asxl1. The mutant form of ASXL1 had no ability to interact with BMI1 as opposed to wild-type ASXL1 protein. Restoration of HSC pool and amelioration of increased apoptosis in hematopoietic stem and progenitor cells were obtained fromAsxl1G643fs/+mice heterozygous forp16Ink4a. These results indicated that loss of protein interaction between Asxl1 mutant and Bmi1 affected the activity of PRC1, and subsequent derepression ofp16Ink4aby aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes inAsxl1G643fs/+mice. This model provides a useful platform to unveil the molecular basis for hematological disorders induced byASXL1mutation and to develop therapeutic strategies for these patients.