The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation.
The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation.
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DOI：
10.1016/j.ccell.2018.08.015
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发表时间：
2018-10-08
期刊：
影响因子：
50.3
通讯作者：
Heidenreich O
中科院分区：
文献类型：
--
作者：
Martinez-Soria N;McKenzie L;Draper J;Ptasinska A;Issa H;Potluri S;Blair HJ;Pickin A;Isa A;Chin PS;Tirtakusuma R;Coleman D;Nakjang S;Assi S;Forster V;Reza M;Law E;Berry P;Mueller D;Osborne C;Elder A;Bomken SN;Pal D;Allan JM;Veal GJ;Cockerill PN;Wichmann C;Vormoor J;Lacaud G;Bonifer C;Heidenreich O
致癌转录因子，如驱动t（8;21）急性髓性白血病（AML）的白血病融合蛋白RUNX1/ETO，构成了癌症特异性但极具挑战性的治疗靶点。我们使用表观基因组分析数据进行RNAi筛选，以询问维持t(8;21) AML的转录网络。该策略确定了细胞周期蛋白D2 （CCND2）是RUNX1/ eto驱动的白血病传播的关键递质。RUNX1/ETO与AP-1协同驱动CCND2表达。经批准的药物敲低或药理学抑制CCND2可显著损害患者源性AML细胞的白血病扩增和在免疫缺陷小鼠宿主中的植入。我们的数据表明，RUNX1/ETO通过促进细胞周期进展来维持白血病，并确定G1 CCND-CDK复合物是治疗RUNX1/ETO驱动的AML的有希望的治疗靶点。RNAi筛选发现CCND2是RUNX1/ETO的关键转录靶点RUNX1/ETO通过与上游元件结合促进CCND2表达，CCND2在体外抑制RUNX1/ETO驱动的白血病扩张，而在体内表达RUNX1/ETO的白血病细胞对CDK4/6抑制剂高度敏感。利用体外和体内筛选确定AML中必要的RUNX1/ETO转录靶点，马丁内斯-索利亚发现CCND2是白血病维持和自我更新所必需的。使用CDK4/6抑制剂palbociclib靶向这种依赖性可以延长AML PDX模型的生存期。
Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML. An RNAi screen identifies CCND2 as a crucial transcriptional target of RUNX1/ETO RUNX1/ETO promotes CCND2 expression by binding to an upstream element CCND2 knockdown inhibits RUNX1/ETO-driven leukemic expansion in vitro and in vivo RUNX1/ETO-expressing leukemic cells are highly sensitive to a CDK4/6 inhibitor Using in vitro and in vivo screens to identify essential RUNX1/ETO transcriptional targets in AML, Martinez-Soria identify CCND2 as required for leukemia maintenance and self-renewal. Targeting this dependency using the CDK4/6 inhibitor palbociclib prolongs the survival of AML PDX models.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
30.8
作者：
Faber ZJ;Chen X;Gedman AL;Boggs K;Cheng J;Ma J;Radtke I;Chao JR;Walsh MP;Song G;Andersson AK;Dang J;Dong L;Liu Y;Huether R;Cai Z;Mulder H;Wu G;Edmonson M;Rusch M;Qu C;Li Y;Vadodaria B;Wang J;Hedlund E;Cao X;Yergeau D;Nakitandwe J;Pounds SB;Shurtleff S;Fulton RS;Fulton LL;Easton J;Parganas E;Pui CH;Rubnitz JE;Ding L;Mardis ER;Wilson RK;Gruber TA;Mullighan CG;Schlenk RF;Paschka P;Döhner K;Döhner H;Bullinger L;Zhang J;Klco JM;Downing JR
通讯作者：
Downing JR
影响因子：
8
作者：
Frank, RC;Sun, X;Nimer, SD
通讯作者：
Nimer, SD
影响因子：
20.3
作者：
Heidenreich, O;Krauter, J;Nordheim, A
通讯作者：
Nordheim, A