Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia.
Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia.
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DOI：
10.1182/blood.2021015036
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发表时间：
2022-10-27
期刊：
影响因子：
20.3
通讯作者：
Bomken, Simon
中科院分区：
文献类型：
--
作者：
Tirtakusuma, Ricky;Szoltysek, Katarzyna;Milne, Paul;Grinev, Vasily V.;Ptasinska, Anetta;Chin, Paulynn S.;Meyer, Claus;Nakjang, Sirintra;Hehir-Kwa, Jayne Y.;Williamson, Daniel;Cauchy, Pierre;Keane, Peter;Assi, Salam A.;Ashtiani, Minoo;Kellaway, Sophie G.;Imperato, Maria R.;Vogiatzi, Fotini;Schweighart, Elizabeth K.;Lin, Shan;Wunderlich, Mark;Stutterheim, Janine;Komkov, Alexander;Zerkalenkova, Elena;Evans, Paul;McNeill, Hesta;Elder, Alex;Martinez-Soria, Natalia;Fordham, Sarah E.;Shi, Yuzhe;Russell, Lisa J.;Pal, Deepali;Smith, Alex;Kingsbury, Zoya;Becq, Jennifer;Eckert, Cornelia;Haas, Oskar A.;Carey, Peter;Bailey, Simon;Skinner, Roderick;Miakova, Natalia;Collin, Matthew;Bigley, Venetia;Haniffa, Muzlifah;Marschalek, Rolf;Harrison, Christine J.;Cargo, Catherine A.;Schewe, Denis;Olshanskaya, Yulia;Thirman, Michael J.;Cockerill, Peter N.;Mulloy, James C.;Blair, Helen J.;Vormoor, Josef;Allan, James M.;Bonifer, Constanze;Heidenreich, Olaf;Bomken, Simon
髓系复发可起源于MLL/AF 4 + ALL的不同分化阶段。表观遗传调节因子的失调是基础谱系重编程的基础。融合基因MLL/AF 4定义了前B急性淋巴细胞白血病的高危亚型。复发可能与从急性淋巴细胞白血病到急性髓细胞白血病的谱系转换有关，导致对化疗和免疫疗法的耐药性引起的不良临床结局。在这项研究中，髓样复发与其匹配的淋巴样表现共享癌基因融合断点，并且起源于从未成熟祖细胞到定型B细胞前体的不同分化阶段。谱系转换与染色质可及性的实质性变化和转录程序的重新连接有关，包括选择性剪接。这些发现表明，淋巴谱系分化的执行和维持受损。复发性骨髓表型与染色质修饰剂的表达改变、剪接或突变反复相关，包括编码核小体重塑和脱乙酰化复合物的ATP酶/解旋酶的CHD 4。CHD 4单独或与其他突变的表观遗传修饰剂组合的扰动诱导MLL/AF 4+细胞模型中的髓系基因表达，表明MLL/AF 4白血病中的谱系转换由破坏的表观遗传调控驱动和维持。
Myeloid relapse can originate from various differentiation stages of MLL/AF4+ ALL. Dysregulation of epigenetic regulators underpins fundamental lineage reprogramming. The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programs, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing, or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation.
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影响因子：
46.9
作者：
Bolotin DA;Poslavsky S;Davydov AN;Frenkel FE;Fanchi L;Zolotareva OI;Hemmers S;Putintseva EV;Obraztsova AS;Shugay M;Ataullakhanov RI;Rudensky AY;Schumacher TN;Chudakov DM
通讯作者：
Chudakov DM
影响因子：
16.6
作者：
Jacoby E;Nguyen SM;Fountaine TJ;Welp K;Gryder B;Qin H;Yang Y;Chien CD;Seif AE;Lei H;Song YK;Khan J;Lee DW;Mackall CL;Gardner RA;Jensen MC;Shern JF;Fry TJ
通讯作者：
Fry TJ
婴儿MLL重新培养急性淋巴细胞白血病中体细胞突变的景观。
影响因子：
30.8
作者：
Andersson AK;Ma J;Wang J;Chen X;Gedman AL;Dang J;Nakitandwe J;Holmfeldt L;Parker M;Easton J;Huether R;Kriwacki R;Rusch M;Wu G;Li Y;Mulder H;Raimondi S;Pounds S;Kang G;Shi L;Becksfort J;Gupta P;Payne-Turner D;Vadodaria B;Boggs K;Yergeau D;Manne J;Song G;Edmonson M;Nagahawatte P;Wei L;Cheng C;Pei D;Sutton R;Venn NC;Chetcuti A;Rush A;Catchpoole D;Heldrup J;Fioretos T;Lu C;Ding L;Pui CH;Shurtleff S;Mullighan CG;Mardis ER;Wilson RK;Gruber TA;Zhang J;Downing JR;St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project
通讯作者：
St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project
影响因子：
120.7
作者：
Gentles, Andrew J.;Plevritis, Sylvia K.;Majeti, Ravindra;Alizadeh, Ash A.
通讯作者：
Alizadeh, Ash A.
DOI：
10.1126/science.1251033
发表时间：
2014-09-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chen L;Kostadima M;Martens JHA;Canu G;Garcia SP;Turro E;Downes K;Macaulay IC;Bielczyk-Maczynska E;Coe S;Farrow S;Poudel P;Burden F;Jansen SBG;Astle WJ;Attwood A;Bariana T;de Bono B;Breschi A;Chambers JC;Consortium B;Choudry FA;Clarke L;Coupland P;van der Ent M;Erber WN;Jansen JH;Favier R;Fenech ME;Foad N;Freson K;van Geet C;Gomez K;Guigo R;Hampshire D;Kelly AM;Kerstens HHD;Kooner JS;Laffan M;Lentaigne C;Labalette C;Martin T;Meacham S;Mumford A;Nürnberg S;Palumbo E;van der Reijden BA;Richardson D;Sammut SJ;Slodkowicz G;Tamuri AU;Vasquez L;Voss K;Watt S;Westbury S;Flicek P;Loos R;Goldman N;Bertone P;Read RJ;Richardson S;Cvejic A;Soranzo N;Ouwehand WH;Stunnenberg HG;Frontini M;Rendon A
通讯作者：
Rendon A