Unraveling the Function of RNA-Binding proteins in B-lympoblastic Leukemia

 描述(申请人提供)：在过去的几十年里，儿童B淋巴细胞性白血病(B-ALL)的治疗取得了重大进展。然而，某些B-ALL亚型仍然对当前的治疗方案无效--包括那些携带MLL基因易位的方案。为了针对这些白血病的新途径，我们进行了一项基因表达谱研究，并分析了数据，以期找到影响基因表达的新生物途径，特别是RNA结合蛋白(RBPs)。限制性商业惯例介导了一系列不同的细胞功能，但许多限制性商业惯例通过调节mRNA和/或翻译的稳定性在基因表达调控中发挥重要作用。有趣的是，我们发现其中一种限制性商业惯例，胰岛素样生长因子2mRNA结合蛋白3(IGF2BP3)，在伴有MLL基因易位的B淋巴母细胞白血病中高度上调，并且与正常B细胞前体细胞相比，该蛋白在患者样本中过度表达。已知IGF2BP3在某些上皮性恶性肿瘤中具有促进生长的作用，但缺乏体内研究。根据我们的初步发现，我们假设IGF2BP3在造血系统中是致癌的，它是B-ALL细胞生存所必需的。在这里，我们将测试该蛋白是否足以在体内的造血系统中产生肿瘤，是否对白血病和正常B细胞的生长和生存是必需的，并确定其下游靶点。这些目标的完成将增加我们对限制性商业惯例在B白血病发生中的理解，并为治疗伴有MLL易位的B-ALL指明了一种新的治疗方式。

 DESCRIPTION (provided by applicant): Major strides have been made in the treatment pediatric B-lymphoblastic leukemia (B-ALL) in the past several decades. Yet, certain subtypes of B-ALL remain refractory to current regimens- including those that carry translocations of the MLL gene. To target novel pathways in these leukemias, we undertook a gene expression profiling study and analyzed the data with a view towards novel biological pathways that affect gene expression, particularly RNA binding proteins (RBPs). RBPs mediate a diverse set of cellular functions, but many have a significant function in gene expression regulation by regulating stability of mRNA and/or translation. Interestingly, we found that one of these RBPs, insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), is highly upregulated in B-lymphoblastic leukemia with translocations of the MLL gene, and that this protein is overexpressed in patient samples when compared with normal B-cell progenitors. IGF2BP3 is known to have a growth-promoting role in certain epithelial malignancies, but in vivo studies are lacking. Based on our preliminary findings, we hypothesize that IGF2BP3 is oncogenic in the hematopoietic system and that it is required for the survival of B-ALL cells. Here, we will test whether this protein is sufficient for oncogenesis in the hematopoietic system in vivo, whether it is required for the growth and survival of leukemic and normal B-cells, and to define its downstream targets. The completion of these aims will increase our understanding of RBPs in B-leukemogenesis, and point to a new therapeutic modality in treating B-ALL with MLL translocations.