在急性髓系白血病（AML）中，以inv（3）（q21q26）或t（3;3）（q21;q26）为代表的EVI1重排通过增强子的结构重排导致EVI1过度表达，并导致不良预后。我和我的同事对 EVI1 重排的骨髓肿瘤进行了突变分析，并确定核心 RNA 剪接因子 SF3B1 是最常见的共突变基因。事实上，携带人源化 inv(3)(q21q26) 等位基因的转基因小鼠中潜伏性白血病的发展因 Sf3b1 突变的共存而显着加速。有趣的是，我们发现这种SF3B1突变体诱导了EVI1本身的错误剪接，从而产生了异常的EVI1亚型，在EVI1的DNA结合域附近框内插入了6个氨基酸。这种异常的EVI1异构体表现出与野生型EVI1不同的DNA结合活性，并显着增强了小鼠造血干细胞的自我更新能力。我们还鉴定了 SF3B1 突变体诱导的 EVI1 错误剪接所需的神秘分支点和外显子剪接增强子。这些数据为进一步阐明EVI1重排AML的分子机制和潜在的治疗候选者提供了基础。

In acute myeloid leukemia (AML), EVI1 rearrangement represented by inv(3)(q21q26) or t(3;3)(q21;q26) causes EVI1 overexpression via structural rearrangement of an enhancer, and confers poor prognosis. My colleagues and I performed a mutational analysis of EVI1-rearranged myeloid neoplasms and identified SF3B1, a core RNA splicing factor, as the most commonly co-mutated gene. Indeed, latent leukemia development in transgenic mice bearing the humanized inv(3)(q21q26) allele was significantly accelerated by co-occurrence of Sf3b1 mutation. Intriguingly, we found that this SF3B1 mutant induced mis-splicing of EVI1 itself, which generated an aberrant EVI1 isoform with in-frame insertion of 6 amino acids near the DNA-binding domain of EVI1. This aberrant EVI1 isoform exhibited DNA-binding activity different from wild-type EVI1 and significantly enhanced the self-renewal capacity of murine hematopoietic stem cells. We also identified the cryptic branch point and exonic splicing enhancer required for this EVI1 mis-splicing induced by the SF3B1 mutant. These data provide a basis for further elucidation of the molecular mechanism and potential therapeutic candidates for EVI1-rearranged AML.