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

• Applicant: Dr. Caroline Pabst
• Subject Area: Hematology, Oncology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432162565

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.

• DFG Programme: Research Grants