RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation
RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation
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DOI：
10.1172/jci80046
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发表时间：
2016-04-01
影响因子：
15.9
通讯作者：
Rao, Dinesh S.
中科院分区：
文献类型：
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作者：
Palanichamy, Jayanth Kumar;Tran, Tiffany M.;Rao, Dinesh S.
基因表达的转录后控制对于确定正常和病理细胞表型都很重要。在体外，rna结合蛋白（rbp）最近被证明在转录后调控中发挥重要作用；然而，rbp对细胞规格的贡献尚不清楚。在这里，我们确定RBP胰岛素样生长因子2 mrna结合蛋白3 （IGF2BP3）在混合谱系白血病重排（mll -重排）b -急性淋巴细胞白血病（B-ALL）中特异性过表达，B-ALL是这种恶性肿瘤的一种亚型，预后差，复发风险高。IGF2BP3是B-ALL细胞系存活所必需的，因为敲低IGF2BP3会导致增殖减少和凋亡增加。IGF2BP3的强制表达使小鼠骨髓细胞具有强大的生存优势，导致造血干细胞和祖细胞的增殖，并使造血发育向B细胞/骨髓谱系倾斜。交联免疫沉淀和高通量测序揭示了igf2bp3调控的转录组，其中包括癌基因MYC和CDK6作为直接靶点。IGF2BP3通过靶向3‘非翻译区（3’ utr）内的元件调节转录本，在小鼠中强制表达IGF2BP3导致BM中Myc和Cdk6的表达增强。总之，我们的数据表明，IGF2BP3介导的靶向致癌转录物可能代表了mll重排B-ALL的关键发病机制，并支持IGF2BP3及其同源rna结合伙伴作为该疾病的潜在治疗靶点。
Posttranscriptional control of gene expression is important for defining both normal and pathological cellular phenotypes. In vitro, RNA-binding proteins (RBPs) have recently been shown to play important roles in posttranscriptional regulation; however, the contribution of RBPs to cell specification is not well understood. Here, we determined that the RBP insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is specifically overexpressed in mixed lineage leukemia-rearranged (MLL-rearranged) B-acute lymphoblastic leukemia (B-ALL), which constitutes a subtype of this malignancy associated with poor prognosis and high risk of relapse. IGF2BP3 was required for the survival of B-ALL cell lines, as knockdown led to decreased proliferation and increased apoptosis. Enforced expression of IGF2BP3 provided murine BM cells with a strong survival advantage, led to proliferation of hematopoietic stem and progenitor cells, and skewed hematopoietic development to the B cell/myeloid lineage. Cross-link immunoprecipitation and high throughput sequencing uncovered the IGF2BP3-regulated transcriptome, which includes oncogenes MYC and CDK6 as direct targets. IGF2BP3 regulated transcripts via targeting elements within 3' untranslated regions (3'UTR), and enforced IGF2BP3 expression in mice resulted in enhanced expression of Myc and Cdk6 in BM. Together, our data suggest that IGF2BP3-mediated targeting of oncogenic transcripts may represent a critical pathogenetic mechanism in MLL-rearranged B-ALL and support IGF2BP3 and its cognate RNA-binding partners as potential therapeutic targets in this disease.