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Gain-of-function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies
Blood ( IF 20.3 ) Pub Date : 2018-01-18 , DOI: 10.1182/blood-2017-06-789669
Hui Yang 1, 2 , Stefan Kurtenbach 1, 3 , Ying Guo 1, 2 , Ines Lohse 1, 4 , Michael A Durante 1, 3 , Jianping Li 1, 2 , Zhaomin Li 1, 2 , Hassan Al-Ali 1, 5 , Lingxiao Li 1, 6 , Zizhen Chen 7 , Matthew G Field 1, 3 , Peng Zhang 1, 2 , Shi Chen 1, 2 , Shohei Yamamoto 1, 2 , Zhuo Li 1, 2 , Yuan Zhou 7 , Stephen D Nimer 1, 2, 6 , J William Harbour 1, 2, 3 , Claes Wahlestedt 1, 4 , Mingjiang Xu 1, 2 , Feng-Chun Yang 1, 2
Affiliation  

Additional Sex Combs-Like 1 (ASXL1) is mutated at a high frequency in all forms of myeloid malignancies associated with poor prognosis. We generated a Vav1 promoter-driven Flag-Asxl1Y588X transgenic mouse model, Asxl1Y588X Tg, to express a truncated FLAG-ASXL1aa1-587 protein in the hematopoietic system. The Asxl1Y588X Tg mice had an enlarged hematopoietic stem cell (HSC) pool, shortened survival, and predisposition to a spectrum of myeloid malignancies, thereby recapitulating the characteristics of myeloid malignancy patients with ASXL1 mutations. ATAC- and RNA-sequencing analyses revealed that the ASXL1aa1-587 truncating protein expression results in more open chromatin in cKit+ cells compared with wild-type cells, accompanied by dysregulated expression of genes critical for HSC self-renewal and differentiation. Liquid chromatography-tandem mass spectrometry and coimmunoprecipitation experiments showed that ASXL1aa1-587 acquired an interaction with BRD4. An epigenetic drug screening demonstrated a hypersensitivity of Asxl1Y588X Tg bone marrow cells to BET bromodomain inhibitors. This study demonstrates that ASXL1aa1-587 plays a gain-of-function role in promoting myeloid malignancies. Our model provides a powerful platform to test therapeutic approaches of targeting the ASXL1 truncation mutations in myeloid malignancies.

中文翻译:

ASXL1截短蛋白在髓系恶性肿瘤发病机制中的功能获得

Additional Sex Combs-Like 1 (ASXL1) 在与预后不良相关的所有形式的髓系恶性肿瘤中发生高频率突变。我们生成了一个 Vav1 启动子驱动的 Flag-Asxl1Y588X 转基因小鼠模型 Asxl1Y588X Tg,以在造血系统中表达截短的 FLAG-ASXL1aa1-587 蛋白。Asxl1Y588X Tg 小鼠具有扩​​大的造血干细胞 (HSC) 池、缩短的生存期和对一系列髓系恶性肿瘤的易感性,从而概括了具有 ASXL1 突变的髓系恶性肿瘤患者的特征。ATAC 和 RNA 测序分析显示,与野生型细胞相比,ASXL1aa1-587 截断蛋白表达导致 cKit+ 细胞中染色质更开放,并伴有对 HSC 自我更新和分化至关重要的基因表达失调。液相色谱-串联质谱和免疫共沉淀实验表明,ASXL1aa1-587 与 BRD4 发生了相互作用。表观遗传药物筛选表明 Asxl1Y588X Tg 骨髓细胞对 BET 溴结构域抑制剂过敏。该研究表明 ASXL1aa1-587 在促进髓系恶性肿瘤中发挥功能获得作用。我们的模型提供了一个强大的平台来测试针对骨髓恶性肿瘤中 ASXL1 截断突变的治疗方法。该研究表明 ASXL1aa1-587 在促进髓系恶性肿瘤中发挥功能获得作用。我们的模型提供了一个强大的平台来测试针对骨髓恶性肿瘤中 ASXL1 截断突变的治疗方法。该研究表明 ASXL1aa1-587 在促进髓系恶性肿瘤中发挥功能获得作用。我们的模型提供了一个强大的平台来测试针对骨髓恶性肿瘤中 ASXL1 截断突变的治疗方法。
更新日期:2018-01-18
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