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Epigenetic regulation of noncanonical menin targets modulates menin inhibitor response in acute myeloid leukemia
Blood ( IF 21.0 ) Pub Date : 2024-08-21 , DOI: 10.1182/blood.2023023644
Xinyue Zhou 1 , Lixia Zhang 1 , Sajesan Aryal 1 , Virginia Veasey 1 , Amanda Tajik 2 , Cecilia Restelli 2 , Steven Moreira 2 , Pengcheng Zhang 1 , Yanfeng Zhang 1 , Kristin Hope 2 , Yang Zhou 1 , Changde Cheng 1 , Ravi Bhatia 1 , Rui Lu 1
Blood ( IF 21.0 ) Pub Date : 2024-08-21 , DOI: 10.1182/blood.2023023644
Xinyue Zhou 1 , Lixia Zhang 1 , Sajesan Aryal 1 , Virginia Veasey 1 , Amanda Tajik 2 , Cecilia Restelli 2 , Steven Moreira 2 , Pengcheng Zhang 1 , Yanfeng Zhang 1 , Kristin Hope 2 , Yang Zhou 1 , Changde Cheng 1 , Ravi Bhatia 1 , Rui Lu 1
Affiliation
Menin inhibitors that disrupt the menin-MLL interaction hold promise for treating specific acute myeloid leukemia (AML) subtypes, including those with KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncovered a potential resistance mechanism independent of canonical menin-MLL targets. We show that a group of noncanonical menin targets, which are bivalently cooccupied by active menin and repressive H2AK119ub marks, are typically downregulated after menin inhibition. Loss of polycomb repressive complex 1.1 (PRC1.1) subunits, such as polycomb group ring finger 1 (PCGF1) or BCL6 corepressor (BCOR), leads to menin inhibitor resistance by epigenetic reactivation of these noncanonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficient leukemia cells to menin inhibition. Moreover, we demonstrate that leukemia cells with the loss of PRC1.1 subunits exhibit reduced monocytic gene signatures and are susceptible to BCL2 inhibition, and that combinational treatment with venetoclax overcomes the resistance to menin inhibition in PRC1.1-deficient leukemia cells. These findings highlight the important roles of PRC1.1 and its regulated noncanonical menin targets in modulating the menin inhibitor response and provide potential strategies to treat leukemia with compromised PRC1.1 function.
中文翻译:
非经典 menin 靶标的表观遗传调控调节急性髓系白血病患者的 menin 抑制剂反应
破坏 menin-MLL 相互作用的 menin 抑制剂有望治疗特定的急性髓性白血病 (AML) 亚型,包括具有 KMT2A 重排 (KMT2A-r) 的亚型,但耐药性仍然是一个挑战。在这里,通过系统地以染色质为中心的 CRISPR 筛选,以及对各种人类和小鼠 KMT2A-r AML 模型的遗传、表观遗传学和药理学研究,我们发现了一种独立于典型 menin-MLL 靶点的潜在耐药机制。我们表明,一组非经典 menin 靶标被活性 menin 和抑制性 H2AK119ub 标记二价共占据,通常在 menin 抑制后下调。多梳抑制复合物 1.1 (PRC1.1) 亚基的缺失,例如多梳组无名指 1 (PCGF1) 或 BCL6 辅阻遏蛋白 (BCOR),通过这些非经典靶标(包括 MYC)的表观遗传再激活导致 menin 抑制剂耐药。MYC 的遗传和药理学抑制可使 PRC1.1 缺陷的白血病细胞对 menin 抑制重新敏感。此外,我们证明 PRC1.1 亚基缺失的白血病细胞表现出单核细胞基因特征降低并且易受 BCL2 抑制,并且与维奈托克联合治疗克服了 PRC1.1 缺陷白血病细胞对 menin 抑制的耐药性。这些发现强调了 PRC1.1 及其调节的非经典 menin 靶点在调节 menin 抑制反应中的重要作用,并为治疗 PRC1.1 功能受损的白血病提供了潜在策略。
更新日期:2024-08-21
中文翻译:
非经典 menin 靶标的表观遗传调控调节急性髓系白血病患者的 menin 抑制剂反应
破坏 menin-MLL 相互作用的 menin 抑制剂有望治疗特定的急性髓性白血病 (AML) 亚型,包括具有 KMT2A 重排 (KMT2A-r) 的亚型,但耐药性仍然是一个挑战。在这里,通过系统地以染色质为中心的 CRISPR 筛选,以及对各种人类和小鼠 KMT2A-r AML 模型的遗传、表观遗传学和药理学研究,我们发现了一种独立于典型 menin-MLL 靶点的潜在耐药机制。我们表明,一组非经典 menin 靶标被活性 menin 和抑制性 H2AK119ub 标记二价共占据,通常在 menin 抑制后下调。多梳抑制复合物 1.1 (PRC1.1) 亚基的缺失,例如多梳组无名指 1 (PCGF1) 或 BCL6 辅阻遏蛋白 (BCOR),通过这些非经典靶标(包括 MYC)的表观遗传再激活导致 menin 抑制剂耐药。MYC 的遗传和药理学抑制可使 PRC1.1 缺陷的白血病细胞对 menin 抑制重新敏感。此外,我们证明 PRC1.1 亚基缺失的白血病细胞表现出单核细胞基因特征降低并且易受 BCL2 抑制,并且与维奈托克联合治疗克服了 PRC1.1 缺陷白血病细胞对 menin 抑制的耐药性。这些发现强调了 PRC1.1 及其调节的非经典 menin 靶点在调节 menin 抑制反应中的重要作用,并为治疗 PRC1.1 功能受损的白血病提供了潜在策略。