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

揭示 B 淋巴细胞白血病中 RNA 结合蛋白的功能

基本信息

批准号：
9101638
负责人：
Dinesh S Rao
金额：
$ 16.75万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9101638
关键词：
Acute Lymphocytic Leukemia Address Affect American Architecture B lymphoid malignancy B-Cell Acute Lymphoblastic Leukemia B-Cell Development B-Lymphocytes Binding Binding Proteins Binding Sites Biological Cell Cycle Cell Line Cell Lineage Cell physiology Cells Childhood Chromatin Classification Complex Data Data Analyses Development Developmental Process Diagnosis Disease Elements Epithelial Epithelial Neoplasms Future Gene Expression Gene Expression Profiling Gene Expression Regulation Gene Proteins Genetic Translation Growth Health Heart Hematopoietic System Insulin-Like Growth Factor II Lymphoblastic Leukemia Lymphopoiesis MLL gene Malignant Neoplasms Mediating Messenger RNA MicroRNAs Modality Molecular Oncogenes Oncogenic Pathogenesis Pathway interactions Patients Phenotype Play Post-Transcriptional Regulation Problem Solving Protein translocation Proteins RNA RNA-Binding Proteins Refractory Regimen Regulation Role Sampling Techniques Testing Therapeutic Translations United States Untranslated RNA Up-Regulation base cancer cell cellular targeting design disorder subtype improved in vivo insight knock-down leukemia leukemogenesis mRNA Stability novel novel strategies novel therapeutics outcome forecast overexpression progenitor promoter public health relevance transcription factor tumorigenesis

项目摘要

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.

描述（由适用提供）：在过去的几十年中，在儿科B-蛋白白血病（B-All）中进行了主要条纹。然而，某些B-ALL的亚型仍然对当前方案（包括携带MLL基因易位的方案）难治性。为了靶向这些白血病中的新途径，我们进行了一项基因表达分析研究，并分析了数据，以朝着影响基因表达的新型生物学途径，尤其是RNA结合蛋白（RBP）。 RBP介导一组潜水的细胞功能，但许多人通过控制mRNA和/或翻译的稳定性在基因表达调节中具有重要功能。有趣的是，我们发现其中一种RBP，类似胰岛素样生长因子2 mRNA结合蛋白3（IGF2BP3）在B-蛋白质细胞白血病中具有高度更新，并与MLL基因的翻译进行了翻译，并且与正常的B细胞相比，该蛋白在患者样品中在患者样品中过表达。众所周知，IGF2BP3在某些上皮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，并且是B-All细胞存活所必需的。在这里，我们将测试该蛋白在体内是否足以在造血系统中发生肿瘤，是否需要白血病的生长和存活并定义其下游靶标。这些目标的完成将增加我们对B-Leukemogeny中RBP的理解，并指出使用MLL易位治疗B-All的新治疗方式。