Abstract：
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.
摘要：
在急性髓细胞性白血病（AML）中，inv(3)(q21q26)或t(3;3)(q21;q26)代表的EVI1重排通过增强子的结构重排引起EVI1过表达，并导致预后不良。我和我的同事对EVI1重排的骨髓性肿瘤进行了突变分析，并鉴定了SF3B1，一种核心RNA剪接因子，作为最常见的共同突变基因。的确,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通过Sf3b1突变的共同发生显着加速。有趣的是，我们发现这个SF3B1突变体诱导了EVI1本身的错误剪接，其产生了在EVI1的DNA结合结构域附近具有6个氨基酸的框内插入的异常EVI1同种型。该异常EVI1同种型表现出不同于野生型EVI1的DNA结合活性,并且显著增强小鼠造血干细胞的自我更新能力。我们还鉴定了SF3B1突变体诱导的这种EVI1错误剪接所需的隐蔽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的分子机制和潜在治疗候选物提供了基础。
