Cantilena Sandra, AlAmeri Mohamed, Che Noelia, Williams Owen, de Boer Jasper
Hemispherian AS, 0585 Oslo, Norway.
Cancer Section, Development Biology and Cancer Programme, UCL GOS Institute of Child Health, London WC1N 1EH, UK.
Cancers (Basel). 2024 Nov 29;16(23):4017. doi: 10.3390/cancers16234017.
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很强的一个亚型，其特点是预后差，尽管接受了强化治疗仍频繁复发。针对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已显示出前景。然而，对这些抑制剂的耐药性，通常由menin突变或其他致癌途径驱动，仍然是一个重大挑战。本综述探讨了旨在克服耐药性和改善患者预后的联合疗法。潜在策略包括抑制DOT1L（一种对KMT2A驱动的转录至关重要的组蛋白甲基转移酶）和BRD4（一种转录超级增强子的调节因子）。此外，靶向MYC（一种在KMT2A重排白血病中经常上调的关键癌基因）提供了另一种方法。还探讨了直接抑制KMT2A融合蛋白和c-MYB（一种对白血病干细胞维持至关重要的转录因子）。通过整合这些不同的策略，我们提出了一种全面的治疗模式，该模式针对白血病转录和表观遗传网络的多个点。这些联合方法旨在破坏关键的致癌途径，降低耐药性，并提高治疗效果，最终为KMT2A重排白血病患者提供更持久的缓解和改善生存。
