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Transcriptional plasticity promotes primary and acquired resistance to BET inhibition

机译：转录可塑性促进对BET抑制的主要和获得性抵抗

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摘要

Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukaemia (AML)(1,2), bromodomain and extra terminal protein (BET) inhibitors are being explored as a promising therapeutic avenue in numerous cancers(3-5). While clinical trials have reported single-agent activity in advanced haematological malignancies(6), mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukaemia, here we perform a chromatin-focused RNAi screen in a sensitive MLL-AF9; Nras(G12D)-driven AML mouse model, and investigate dynamic transcriptional profiles in sensitive and resistantmouse and human leukaemias. Our screen shows that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET inhibitor resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodelling of regulatory pathways that restore the transcription of key targets such as Myc. Similarly, while BET inhibition triggers acute MYC repression in human leukaemias regardless of their sensitivity, resistant leukaemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signalling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic chromatin immunoprecipitation sequencing and self-transcribing active regulatory region sequencing of enhancer profiles reveal that BET-resistant states are characterized by remodelled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signalling as a driver and candidate biomarker of primary and acquired BET resistance in leukaemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting resistance to BET inhibitors and, potentially, other chromatin-targeted therapies.
机译：在发现BRD4作为急性髓细胞性白血病（AML）的非致癌基因成瘾靶标后，溴结构域和额外末端蛋白（BET）抑制剂被探索为许多癌症中有希望的治疗途径（3-5） 。尽管临床试验已经报道了晚期血液恶性肿瘤中的单药活性（6），但对BET抑制反应的机制仍知之甚少。为了确定白血病中原发性和获得性BET耐药的相关因素，我们在敏感的MLL-AF9中进行了针对染色质的RNAi筛选； Nras（G12D）驱动的AML小鼠模型，并研究敏感和耐药小鼠以及人类白血病中的动态转录谱。我们的屏幕显示，与其他情况下的作用相反，抑制PRC2复合物可促进AML中的BET抑制剂耐药性。 PRC2抑制并不直接影响对Brd4依赖的转录物的调节，但可促进调节途径的重塑，从而恢复关键靶标（如Myc）的转录。类似地，尽管BET抑制无论其敏感性如何都触发了人类白血病的急性MYC抑制，但耐药性白血病却以其迅速恢复MYC转录的能力为特征。该过程涉及WNT信号传导成分的激活和募集，这补偿了BRD4的丢失和各种癌症模型中的驱动抗性。增强子图谱的动态染色质免疫沉淀测序和自转录活性调控区测序表明，BET耐药状态的特征是重构的调控格局，包括激活了对MYC增强剂的激活，后者响应BET抑制而募集WNT机制。总之，我们的结果确定并验证了WNT信号传导是白血病原发性和获得性BET抗性的驱动器和候选生物标志物，并暗示转录程序的重新布线是促进对BET抑制剂和可能的其他针对染色质的疗法产生抗性的重要机制。

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  • 来源
    《Nature》 |2015年第7570期|543-547|共5页
  • 作者

    Rathert Philipp; Roth Mareike; Neumann Tobias; Muerdter Felix; Roe Jae-Seok; Muhar Matthias; Deswal Sumit; Cerny-Reiterer Sabine; Peter Barbara; Jude Julian; Hoffmann Thomas; Boryn Lukasz M.; Axelsson Elin; Schweifer Norbert; Tontsch-Grunt Ulrike; Dow Lukas E.; Gianni Davide; Pearson Mark; Valent Peter; Stark Alexander; Kraut Norbert; Vakoc Christopher R.; Zuber Johannes;

  • 作者单位

    Vienna Bioctr VBC, Res Inst Mol Pathol IMP, A-1030 Vienna, Austria;

    Vienna Bioctr VBC, Res Inst Mol Pathol IMP, A-1030 Vienna, Austria;

    Vienna Bioctr VBC, Res Inst Mol Pathol IMP, A-1030 Vienna, Austria;

    Vienna Bioctr VBC, Res Inst Mol Pathol IMP, A-1030 Vienna, Austria;

    Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA;

    Vienna Bioctr VBC, Res Inst Mol Pathol IMP, A-1030 Vienna, Austria;

    Vienna Bioctr VBC, Res Inst Mol Pathol IMP, A-1030 Vienna, Austria;

    Med Univ Vienna, Div Hematol & Hemostaseol, Dept Internal Med 1, A-1090 Vienna, Austria|Med Univ Vienna, Ludwig Boltzmann Cluster Oncol, A-1090 Vienna, Austria;

    Med Univ Vienna, Div Hematol & Hemostaseol, Dept Internal Med 1, A-1090 Vienna, Austria|Med Univ Vienna, Ludwig Boltzmann Cluster Oncol, A-1090 Vienna, Austria;

    Vienna Bioctr VBC, Res Inst Mol Pathol IMP, A-1030 Vienna, Austria;

    Vienna Bioctr VBC, Res Inst Mol Pathol IMP, A-1030 Vienna, Austria;

    Vienna Bioctr VBC, Res Inst Mol Pathol IMP, A-1030 Vienna, Austria;

    Vienna Bioctr VBC, Res Inst Mol Pathol IMP, A-1030 Vienna, Austria;

    Boehringer Ingelheim Reg Ctr Vienna GmbH, A-1121 Vienna, Austria;

    Boehringer Ingelheim Reg Ctr Vienna GmbH, A-1121 Vienna, Austria;

    Weill Cornell Med Coll, Dept Med Hematol & Med Oncol, New York, NY 10065 USA;

    Boehringer Ingelheim Reg Ctr Vienna GmbH, A-1121 Vienna, Austria;

    Boehringer Ingelheim Reg Ctr Vienna GmbH, A-1121 Vienna, Austria;

    Med Univ Vienna, Div Hematol & Hemostaseol, Dept Internal Med 1, A-1090 Vienna, Austria|Med Univ Vienna, Ludwig Boltzmann Cluster Oncol, A-1090 Vienna, Austria;

    Vienna Bioctr VBC, Res Inst Mol Pathol IMP, A-1030 Vienna, Austria;

    Boehringer Ingelheim Reg Ctr Vienna GmbH, A-1121 Vienna, Austria;

    Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA;

    Vienna Bioctr VBC, Res Inst Mol Pathol IMP, A-1030 Vienna, Austria;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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