ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine.
ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine.
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DOI：
10.1038/s41408-021-00541-0
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发表时间：
2021-09-21
影响因子：
12.8
通讯作者：
Verma A
中科院分区：
文献类型：
--
作者：
Rahmani NE;Ramachandra N;Sahu S;Gitego N;Lopez A;Pradhan K;Bhagat TD;Gordon-Mitchell S;Pena BR;Kazemi M;Rao K;Giricz O;Maqbool SB;Olea R;Zhao Y;Zhang J;Dolatshad H;Tittrea V;Tatwavedi D;Singh S;Lee J;Sun T;Steidl U;Shastri A;Inoue D;Abdel-Wahab O;Pellagatti A;Gavathiotis E;Boultwood J;Verma A
Bcl2抑制剂VEN与DNMT抑制剂azacytidine(AZA)联合应用显示出显著的抗白血病效果。为了探索突变白血病细胞对VEN和AZA选择性敏感性的机制，我们使用了基于细胞的等基因模型，该模型包含表观遗传调节因子ASXL1中的一个常见的白血病相关突变。与未校正的KBM5细胞相比，经CRISPR/Cas9介导的ASXL1G710X突变校正的KBM5细胞在体外显示出白血病生长抑制，髓系分化增加，HOXA和BCL2基因表达降低。与野生型MDS患者的CD34+细胞相比，ASXL1突变MDS患者的骨髓CD34+细胞中抗凋亡基因BCL2的表达也增加。ATAC-测序显示ASXL1突变KBM5细胞中BCL2启动子的染色质是开放的。BH3图谱显示突变细胞对BCL2的依赖性增加。经VEN处理后，突变细胞的生长抑制增强。此外，对原代MDS样本和等基因细胞系的全基因组甲基组分析表明，ASXL1突变细胞中的基因体甲基化增加，从而增加了对AZA的敏感性。这些数据从机制上将常见的白血病相关突变ASXL1与VEN和AZA的敏感性增强联系在一起，这是通过表观遗传上调BCL2表达和DNA甲基化的广泛变化来实现的。
The BCL2-inhibitor, Venetoclax (VEN), has shown significant anti-leukemic efficacy in combination with the DNMT-inhibitor, Azacytidine (AZA). To explore the mechanisms underlying the selective sensitivity of mutant leukemia cells to VEN and AZA, we used cell-based isogenic models containing a common leukemia-associated mutation in the epigenetic regulator ASXL1. KBM5 cells with CRISPR/Cas9-mediated correction of the ASXL1G710X mutation showed reduced leukemic growth, increased myeloid differentiation, and decreased HOXA and BCL2 gene expression in vitro compared to uncorrected KBM5 cells. Increased expression of the anti-apoptotic gene, BCL2, was also observed in bone marrow CD34+ cells from ASXL1 mutant MDS patients compared to CD34+ cells from wild-type MDS cases. ATAC-sequencing demonstrated open chromatin at the BCL2 promoter in the ASXL1 mutant KBM5 cells. BH3 profiling demonstrated increased dependence of mutant cells on BCL2. Upon treatment with VEN, mutant cells demonstrated increased growth inhibition. In addition, genome-wide methylome analysis of primary MDS samples and isogenic cell lines demonstrated increased gene-body methylation in ASXL1 mutant cells, with consequently increased sensitivity to AZA. These data mechanistically link the common leukemia-associated mutation ASXL1 to enhanced sensitivity to VEN and AZA via epigenetic upregulation of BCL2 expression and widespread alterations in DNA methylation.
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影响因子：
46.9
作者：
Ball, Madeleine P.;Li, Jin Billy;Gao, Yuan;Lee, Je-Hyuk;LeProust, Emily M.;Park, In-Hyun;Xie, Bin;Daley, George Q.;Church, George M.
通讯作者：
Church, George M.
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
23.9
作者：
Lagadinou, Eleni D.;Sach, Alexander;Callahan, Kevin;Rossi, Randall M.;Neering, Sarah J.;Minhajuddin, Mohammad;Ashton, John M.;Pei, Shanshan;Grose, Valerie;O'Dwyer, Kristen M.;Liesveld, Jane L.;Brookes, Paul S.;Becker, Michael W.;Jordan, Craig T.
通讯作者：
Jordan, Craig T.
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：
28.2
作者：
Pan R;Hogdal LJ;Benito JM;Bucci D;Han L;Borthakur G;Cortes J;DeAngelo DJ;Debose L;Mu H;Döhner H;Gaidzik VI;Galinsky I;Golfman LS;Haferlach T;Harutyunyan KG;Hu J;Leverson JD;Marcucci G;Müschen M;Newman R;Park E;Ruvolo PP;Ruvolo V;Ryan J;Schindela S;Zweidler-McKay P;Stone RM;Kantarjian H;Andreeff M;Konopleva M;Letai AG
通讯作者：
Letai AG