The role of the RNA binding protein RBM4 on leukemic stem cell activity in acute myeloid leukemia.

RNA结合蛋白RBM4对急性髓系白血病白血病干细胞活性的作用。

• 批准号: 432162565
• 负责人: Dr. Caroline Pabst
• 金额: --
• 依托单位: Klinik für Hämatologie, Onkologie und Rheumatologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/432162565?language=en
• 关键词: role; RNA; binding; protein; RBM4

Dysregulation of alternative splicing (AS) is a major pathomechanism in the development of acute myeloid leukemia (AML). AS can lead to increased activity of oncogenes through the use of alternative exons, but also result in reduced activity of tumor suppressor genes through intron retention. RNA binding proteins (RBPs) are an integral part of the splicing machinery. In our preliminary work, we identified 5 RBPs that were overexpressed in AML samples that had a particularly high leukemia stem cell (LSC) content. Of these five, only RBM4 showed a significant association with poor survival and a particularly strong pro-differentiating phenotype in human CD34+ cells. We therefore hypothesize that RBM4 is essential for the self-renewal of HSCs and LSCs. We aim to examine these as follows: Analysis of the phenotype of RBM4 Knockdown (KD) in primary AML samples, RBM4-regulated AS mechanisms (RNA sequencing), and identification of binding partners, "target" RNAs, and RBM4-regulated differentiation pathways as potential new therapeutic targets.

选择性剪接（AS）异常是急性髓系白血病（AML）发生发展的主要病理机制。AS可以通过使用替代外显子导致癌基因活性增加，但也可以通过内含子保留导致肿瘤抑制基因活性降低。RNA结合蛋白（RBP）是剪接机制的组成部分。在我们的初步工作中，我们确定了5种在白血病干细胞（LSC）含量特别高的AML样本中过表达的RBP。在这五种细胞中，只有RBM4显示出与人CD34+细胞中的较差存活率和特别强的促分化表型显著相关。因此，我们假设RBM4对于HSC和LSC的自我更新是必不可少的。我们的目的是检查这些如下：在原发性AML样本中RBM4敲低（KD）的表型分析，RBM4调节的AS机制（RNA测序），并确定结合伴侣，“靶”RNA和RBM4调节的分化途径作为潜在的新的治疗靶点。