Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drives inv(3)/t(3;3) myeloid leukemias via structural rearrangement of an enhancer that upregulates transcription of EVI1. Here, we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 that is frequently present in inv(3)/t(3;3) acute myeloid leukemia (AML) and directly contributes to leukemic transformation. This EVI1 isoform is generated by oncogenic mutations in the core RNA splicing factor SF3B1, which is mutated in >30% of inv(3)/t(3;3) myeloid neoplasm patients and thereby represents the single most commonly cooccurring genomic alteration in inv(3)/t(3;3) patients. SF3B1 mutations are statistically uniquely enriched in inv(3)/t(3;3) myeloid neoplasm patients and patient-derived cell lines compared with other forms of AML and promote mis-splicing of EVI1 generating an in-frame insertion of 6 amino acids at the 3' end of the second zinc finger domain of EVI1. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells, and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21q26) allele resulted in generation of this novel EVI1 isoform in mice and hastened leukemogenesis in vivo. The mutant SF3B1 spliceosome depends upon an exonic splicing enhancer within EVI1 exon 13 to promote usage of a cryptic branch point and aberrant 3' splice site within intron 12 resulting in the generation of this isoform. These data provide a mechanistic basis for the frequent cooccurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).

中文翻译：

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异常的 EVI1 剪接导致 EVI1 重排白血病。


MECOM（MDS1 和 EVI1 复合位点）的详细基因组和表观基因组分析表明，3 号染色体的倒位或易位通过上调 EVI1 转录的增强子的结构重排驱动 inv(3)/t(3;3) 骨髓性白血病。在这里，我们发现了一种新的、先前未注释的致癌 RNA 剪接衍生的 EVI1 异构体，它经常存在于 inv(3)/t(3;3) 急性髓系白血病 (AML) 中，并直接导致白血病转化。这种 EVI1 亚型是由核心 RNA 剪接因子 SF3B1 的致癌突变产生的，该因子在超过 30% 的 inv(3)/t(3;3) 骨髓肿瘤患者中发生突变，因此代表了 inv 中最常见的单一基因组改变。 (3)/t(3;3) 名患者。与其他形式的 AML 相比，SF3B1 突变在 inv(3)/t(3;3) 骨髓肿瘤患者和患者来源的细胞系中具有统计上独特的富集性，并促进 EVI1 的错误剪接，产生 6 个氨基酸的框内插入位于 EVI1 第二个锌指结构域的 3' 端。这种EVI1剪接变体的表达增强了造血干细胞的自我更新，并且在携带人源化inv(3)(q21q26)等位基因的小鼠中引入突变体SF3B1导致了这种新型EVI1亚型在小鼠中的产生并加速了体内白血病的发生。突变体 SF3B1 剪接体依赖于 EVI1 外显子 13 内的外显子剪接增强子，以促进内含子 12 内隐秘分支点和异常 3' 剪接位点的使用，从而导致该亚型的产生。这些数据为SF3B1突变的频繁共存提供了机制基础，并为携带inv(3)/t(3;3)的髓系白血病的发病机制提供了新的见解。