BET inhibitor resistance emerges from leukaemia stem cells.
BET inhibitor resistance emerges from leukaemia stem cells.
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BET抑制剂耐药性来自白血病干细胞。
DOI：
10.1038/nature14888
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发表时间：
2015-09-24
期刊：
影响因子：
64.8
通讯作者：
Dawson MA
中科院分区：
文献类型：
--
作者：
Fong CY;Gilan O;Lam EY;Rubin AF;Ftouni S;Tyler D;Stanley K;Sinha D;Yeh P;Morison J;Giotopoulos G;Lugo D;Jeffrey P;Lee SC;Carpenter C;Gregory R;Ramsay RG;Lane SW;Abdel-Wahab O;Kouzarides T;Johnstone RW;Dawson SJ;Huntly BJ;Prinjha RK;Papenfuss AT;Dawson MA
布罗莫结构域和额外末端蛋白（BET）抑制剂是一流的靶向治疗，通过直接靶向结合乙酰化染色质标记的布罗莫结构域蛋白，提供了新的治疗机会。早期临床试验显示出希望，特别是在急性髓性白血病中，因此评估耐药机制对于优化这些药物的临床疗效至关重要。在这里，我们使用原代小鼠造血干细胞和祖细胞永生化的融合蛋白MLL-AF 9产生几个单细胞克隆，表现出耐药性，在体外和体内，原型BET抑制剂，I-BET。对I-BET的抗性赋予对化学上不同的BET抑制剂如JQ 1的交叉抗性，以及对BET蛋白质的遗传敲低的抗性。耐药性不是通过增加药物外排或代谢介导的，而是显示出从离体和体内的白血病干细胞中出现。染色质结合的BRD 4在耐药细胞中总体减少，而关键靶基因如Myc的表达保持不变，这突出了调节转录的替代机制的存在。我们证明，在人类和小鼠白血病细胞中，对BET抑制剂的抗性部分是Wnt/β-连环蛋白信号传导增加的结果，并且该途径的负调节导致体外和体内对I-BET的敏感性恢复。总之，这些发现为急性髓性白血病的生物学提供了新的见解，突出了BET抑制剂的潜在治疗局限性，并确定了可能增强这些独特靶向治疗临床实用性的策略。
Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic opportunity by directly targeting bromodomain proteins that bind acetylated chromatin marks. Early clinical trials have shown promise, especially in acute myeloid leukaemia, and therefore the evaluation of resistance mechanisms is crucial to optimize the clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem and progenitor cells immortalized with the fusion protein MLL-AF9 to generate several single-cell clones that demonstrate resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism, but is shown to emerge from leukaemia stem cells both ex vivo and in vivo. Chromatin-bound BRD4 is globally reduced in resistant cells, whereas the expression of key target genes such as Myc remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors, in human and mouse leukaemia cells, is in part a consequence of increased Wnt/β-catenin signalling, and negative regulation of this pathway results in restoration of sensitivity to I-BET in vitro and in vivo. Together, these findings provide new insights into the biology of acute myeloid leukaemia, highlight potential therapeutic limitations of BET inhibitors, and identify strategies that may enhance the clinical utility of these unique targeted therapies.
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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
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
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影响因子：
3
作者：
Amarasinghe KC;Li J;Halgamuge SK
通讯作者：
Halgamuge SK
影响因子：
158.5
作者：
Jamieson, CHM;Ailles, LE;Weissman, IL
通讯作者：
Weissman, IL
影响因子：
82.9
作者：
Eppert, Kolja;Takenaka, Katsuto;Dick, John E.
通讯作者：
Dick, John E.