KMT2A-rearranged leukemias are a highly aggressive subset of acute leukemia, characterized by poor prognosis and frequent relapses despite intensive treatment. Menin inhibitors, which target the critical KMT2A–menin interaction driving leukemogenesis, have shown promise in early clinical trials. However, resistance to these inhibitors, often driven by menin mutations or alternative oncogenic pathways, remains a significant challenge. This review explores combination therapies aimed at overcoming resistance and improving patient outcomes. Potential strategies include inhibiting DOT1L, a histone methyltransferase essential for KMT2A-driven transcription, and BRD4, a regulator of transcriptional super-enhancers. Additionally, targeting MYC, a key oncogene frequently upregulated in KMT2A-rearranged leukemia, offers another approach. Direct inhibition of KMT2A-fusion proteins and c-MYB, a transcription factor critical for leukemic stem cell maintenance, is also explored. By integrating these diverse strategies, we propose a comprehensive therapeutic paradigm that targets multiple points of the leukemic transcriptional and epigenetic network. These combination approaches aim to disrupt key oncogenic pathways, reduce resistance, and enhance treatment efficacy, ultimately providing more durable remissions and improved survival for patients with KMT2A-rearranged leukemias.
KMT2A重排白血病是急性白血病中侵袭性极强的亚型，其特点是预后不良，即使接受强化治疗后仍频繁复发。靶向驱动白血病发生的关键KMT2A-menin相互作用的menin抑制剂在早期临床试验中展现出潜力。然而，由menin突变或替代致癌通路驱动的耐药性仍是重大挑战。本综述探讨旨在克服耐药性并改善患者预后的联合治疗策略。潜在策略包括抑制组蛋白甲基转移酶DOT1L（该酶对KMT2A驱动的转录至关重要）和转录超级增强子调节因子BRD4。此外，靶向在KMT2A重排白血病中常过度表达的关键癌基因MYC提供了另一途径。研究还探索了直接抑制KMT2A融合蛋白及对白血病干细胞维持至关重要的转录因子c-MYB。通过整合这些多样化策略，我们提出了一种靶向白血病转录与表观遗传网络多个节点的综合治疗范式。这些联合疗法旨在破坏关键致癌通路、降低耐药性并提升治疗效果，最终为KMT2A重排白血病患者实现更持久的缓解和更优的生存预后。
Synergistic Strategies for KMT2A-Rearranged Leukemias: Beyond Menin Inhibitor
肿瘤(癌症)患者之家