近年来，大规模测序工作已经确定了造血干细胞中的可靶向驱动突变。这些努力导致九种治疗复发或难治性急性髓性白血病（R/R AML）的新药得到开发和批准。然而，尽管靶向治疗不断扩大，但实现 AML 和高危骨髓增生异常综合征 (HR-MDS) 的持久缓解仍然是一项重大挑战，迫切需要新的有效治疗方法。异常 RNA 剪接的调节已成为骨髓疾病的一种新型治疗方法。异常剪接会导致基因表达失调，从而通过增加增殖和转移潜力、免疫逃避、减少细胞凋亡和化疗耐药来促进肿瘤发生。剪接体成分的突变已在多种癌症亚型中被发现，其中 RNA 结合蛋白 SF3B1、SRSF2、U2AF1 和 ZRSR2 的突变经常发生在 AML 和高达 60% 的 MDS 患者以及慢性粒单核细胞白血病和10%的患者患有慢性淋巴细胞白血病。在这篇综述中，我们探讨了针对异常剪接的治疗策略以及这些方法推动临床反应的潜力。© 2024 英国血液学会和 John Wiley

In recent years, large-scale sequencing efforts have identified targetable driver mutations in haematopoietic stem cells. These efforts have led to the development and approval of nine novel agents for relapsed or refractory acute myelogenous leukaemia (R/R AML). However, despite an expansion in targeted therapies, achieving a durable remission in AML and high-risk myelodysplastic syndrome (HR-MDS) remains a significant challenge, and there is an urgent need for new effective treatments. Modulation of aberrant RNA splicing has emerged as a novel therapeutic approach in myeloid diseases. Aberrant splicing drives dysregulated gene expression that promotes tumourigenesis through increased proliferation and metastatic potential, immune evasion, decreased apoptosis, and chemotherapy resistance. Mutations in spliceosomal components have been identified in numerous cancer subtypes, with mutations in RNA binding proteins SF3B1, SRSF2, U2AF1, and ZRSR2 occurring frequently in AML and in up to 60% of patients with MDS, as well as in chronic myelomonocytic leukaemia and in 10% of patients with chronic lymphocytic leukaemia. In this review, we explore therapeutic strategies targeting aberrant splicing and the potential of these approaches to drive clinical responses.© 2024 British Society for Haematology and John Wiley & Sons Ltd.