破坏 Menin-MLL 相互作用的 Menin 抑制剂有望治疗特定的急性髓系白血病亚型，包括 KMT2A 重排 (KMT2A-r)，但耐药性仍然是一个挑战。在这里，通过系统性的以染色质为重点的 CRISPR 筛选，以及在各种人类和小鼠 KMT2A-r AML 模型中进行的遗传、表观遗传和药理学研究，我们发现了一种独立于典型 Menin-MLL 靶标的潜在耐药机制。我们发现，一组非典型 Menin 靶点，由活跃 Menin 和抑制性 H2AK119ub 标记双价共同占据，在 Menin 抑制后通常会下调。 Polycomb 抑制复合物 1.1 (PRC1.1) 亚基（例如 PCGF1 或 BCOR）的丢失，会通过这些非典型靶标（包括 MYC）的表观遗传重新激活而导致 Menin 抑制剂耐药。 MYC 的遗传和药理学抑制可以使 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减少，并且对 BCL2 抑制敏感，而 Venetoclax 的联合治疗克服了 PRC1.1 缺陷的白血病细胞对 Menin 抑制的耐药性。这些发现强调了 PRC1.1 及其受监管的非经典 Menin 靶点在调节 Menin 抑制剂反应中的重要作用，并提供了治疗 PRC1.1 功能受损的白血病的潜在策略。版权所有 © 2024 美国血液学会。

Menin inhibitors that disrupt Menin-MLL interaction hold promise for treating specific acute myeloid leukemia subtypes, including 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 uncover a potential resistance mechanism independent of canonical Menin-MLL targets. We show that a group of non-canonical Menin targets, which are bivalently co-occupied by active Menin and repressive H2AK119ub marks, are typically downregulated following Menin inhibition. The loss of Polycomb Repressive Complex 1.1 (PRC1.1) subunits, such as PCGF1 or BCOR, leads to Menin inhibitor resistance by epigenetic reactivation of these non-canonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficent 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 the BCL2 inhibition, and combinational treatment of 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 non-canonical Menin targets in modulating Menin inhibitor response and provide potential strategies to treat leukemias with compromised PRC1.1 function.Copyright © 2024 American Society of Hematology.