Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia.
Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia.
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DOI：
10.1038/s41467-022-29142-6
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发表时间：
2022-03-17
影响因子：
16.6
通讯作者：
Patnaik MM
中科院分区：
文献类型：
--
作者：
Binder M;Carr RM;Lasho TL;Finke CM;Mangaonkar AA;Pin CL;Berger KR;Mazzone A;Potluri S;Ordog T;Robertson KD;Marks DL;Fernandez-Zapico ME;Gaspar-Maia A;Patnaik MM
髓系肿瘤是一种克隆性造血干细胞疾病，由连续获得的复发性遗传病变驱动。染色质重塑基因ASXL1 （ASXL1MT）的截断突变与一种高风险疾病表型相关，这种表型具有增殖增加、表观遗传治疗耐药性和生存结果差。我们进行了多组学研究，以确定慢性髓单细胞白血病（CMML）中与ASXL1MT相关的基因表达和染色质重塑。ASXL1MT与抑制组蛋白甲基化的缺失和启动子区域允许组蛋白甲基化和乙酰化的增加有关。ASXL1MT进一步与结合ETS转录因子的远端增强子的从头可及性相关，靶向重要的白血病驱动基因。启动子和增强子的染色质重塑与基因表达密切相关，并且在过表达基因之间具有异质性。这些结果提供了ASXL1MT CMML的转录组和染色质全景图，为开发针对致癌顺式相互作用的新治疗策略提供了重要框架。染色质重塑基因ASXL1 （ASXL1MT）的突变与较差的临床结果相关，然而，它们对染色质动力学的影响仍未被探索。在这里，作者使用多组学方法研究慢性髓细胞白血病（CMML），并研究ASXL1MT CMML的转录组和染色质景观。
Myeloid neoplasms are clonal hematopoietic stem cell disorders driven by the sequential acquisition of recurrent genetic lesions. Truncating mutations in the chromatin remodeler ASXL1 (ASXL1MT) are associated with a high-risk disease phenotype with increased proliferation, epigenetic therapeutic resistance, and poor survival outcomes. We performed a multi-omics interrogation to define gene expression and chromatin remodeling associated with ASXL1MT in chronic myelomonocytic leukemia (CMML). ASXL1MT are associated with a loss of repressive histone methylation and increase in permissive histone methylation and acetylation in promoter regions. ASXL1MT are further associated with de novo accessibility of distal enhancers binding ETS transcription factors, targeting important leukemogenic driver genes. Chromatin remodeling of promoters and enhancers is strongly associated with gene expression and heterogenous among overexpressed genes. These results provide a comprehensive map of the transcriptome and chromatin landscape of ASXL1MT CMML, forming an important framework for the development of novel therapeutic strategies targeting oncogenic cis interactions. ‘Mutations in the chromatin remodeler ASXL1 (ASXL1MT) are associated with poor clinical outcome, however, their impact on chromatin dynamics remains unexplored. Here the authors use a multi-omics approach for chronic myelomonocytic leukemia (CMML) and investigate the transcriptome and chromatin landscape of ASXL1MT CMML.
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影响因子：
50.3
作者：
Abdel-Wahab O;Adli M;LaFave LM;Gao J;Hricik T;Shih AH;Pandey S;Patel JP;Chung YR;Koche R;Perna F;Zhao X;Taylor JE;Park CY;Carroll M;Melnick A;Nimer SD;Jaffe JD;Aifantis I;Bernstein BE;Levine RL
通讯作者：
Levine RL
影响因子：
14.9
作者：
Cheneby, Jeanne;Menetrier, Zacharie;Ballester, Benoit
通讯作者：
Ballester, Benoit
影响因子：
16.6
作者：
Asada S;Goyama S;Inoue D;Shikata S;Takeda R;Fukushima T;Yonezawa T;Fujino T;Hayashi Y;Kawabata KC;Fukuyama T;Tanaka Y;Yokoyama A;Yamazaki S;Kozuka-Hata H;Oyama M;Kojima S;Kawazu M;Mano H;Kitamura T
通讯作者：
Kitamura T
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
DOI：
10.1093/database/bax028
发表时间：
2017-01-01
期刊：
Database : the journal of biological databases and curation
影响因子：
--
作者：
Fishilevich S;Nudel R;Rappaport N;Hadar R;Plaschkes I;Iny Stein T;Rosen N;Kohn A;Twik M;Safran M;Lancet D;Cohen D
通讯作者：
Cohen D