Despite recent advances in therapeutic approaches, patients with MLL-rearranged leukemia still have poor outcomes and a high risk of relapse. Here, we found that MLL-AF4, the most common MLL fusion protein in patients, transcriptionally induces IGF2BP3 and that IGF2BP3 strongly amplifies MLL-Af4 mediated leukemogenesis. Deletion of Igf2bp3 significantly increases the survival of mice with MLL-Af4 driven leukemia and greatly attenuates disease, with a minimal impact on baseline hematopoiesis. At the cellular level, MLL-Af4 leukemia-initiating cells require Igf2bp3 for their function in leukemogenesis. eCLIP and transcriptome analysis of MLL-Af4 transformed stem and progenitor cells and MLL-Af4 bulk leukemia cells reveals a complex IGF2BP3-regulated post-transcriptional operon governing leukemia cell survival and proliferation. Regulated mRNA targets include important leukemogenic genes such as those in the Hoxa locus and numerous genes within the Ras signaling pathway. Together, our findings show that IGF2BP3 is an essential positive regulator of MLL-AF4 mediated leukemogenesis and represents an attractive therapeutic target in this disease.

中文翻译：

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RNA结合蛋白IGF2BP3对转录后基因的调控对于MLL-AF4介导的白血病发生至关重要

尽管最近在治疗方法方面取得了进展，但MLL重排的白血病患者的预后仍然很差，复发的风险很高。在这里，我们发现患者中最常见的MLL融合蛋白MLL-AF4在转录上诱导了IGF2BP3，而IGF2BP3强烈扩增了MLL-Af4介导的白血病发生。Igf2bp3的删除显着提高了MLL-Af4驱动的白血病小鼠的存活率，并大大减轻了疾病，对基线造血作用的影响却很小。在细胞水平上，MLL-Af4白血病起始细胞需要Igf2bp3在白血病发生中的作用。对MLL-Af4转化的干细胞和祖细胞以及MLL-Af4大量白血病细胞的eCLIP和转录组分析表明，IGF2BP3调控转录后操纵子的复杂性决定着白血病细胞的存活和增殖。调控的mRNA靶标包括重要的致白血病基因，例如Hoxa基因座中的基因以及Ras信号传导途径中的众多基因。在一起，我们的研究结果表明，IGF2BP3是MLL-AF4介导的白血病发生的基本正调节剂，并且代表了该疾病的诱人治疗靶标。