Project Details
Projekt
Deciphering RBP networks in high-risk subgroups of pediatric ALL and AML
Applicant
Privatdozentin Dr. Jessica Höll
Subject Area
Hematology, Oncology
Pediatric and Adolescent Medicine
Pediatric and Adolescent Medicine
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 468534282
Transcriptional mechanisms in leukemogenesis have been well studied, whereas posttranscriptional gene regulation – especially RNA-binding protein (RBPs)-mediated gene regulation – has been underexplored. Notable exceptions include IGF2BP3 (IGF2 mRNA binding protein 3), which is overexpressed in mixed lineage leukemia-rearranged B-acute lymphoblastic leukemia (ALL) and promotes hematopoietic progenitor proliferation, and MSI2 (Musashi 2), which is an oncogenic driver in AML. However, the oncogenic potential of most of the more than 1500 RBPs has not been analyzed in detail, and especially not in the pediatric patient population. However, as in both, pediatric ALL and especially acute myeloid leukemia (AML), death from intensity-maximized conventional chemotherapies is still unacceptably high, and outcome remains poor in both AML and high-risk ALL. Thus, the identification of new (ideally individualized), targetable structures is the focus of leukemia research.The hypothesis of this proposal is that RBPs as master regulators of post-transcriptional gene regulation play key roles in leukemic transformation and maintenance. Understanding, which RBPs are oncogenic drivers and which sets of (m)RNAs are subsequently dysregulated will prospectively allow for the identification of new targetable proteins or pathways. We have performed RBP-directed CRISPR/Cas9 screens in four AML and ALL cell lines and identified candidate oncogenic RBPs, which we wish to explore further in this proposed project. The aim of the proposed project thus is to (1) validate the essential role of the top candidate RBPs for the maintenance of leukemia. Next, we will (2) elucidate the function of the target RBPs in normal hematopoiesis to understand their putative role in leukemogenesis. Lastly (3), we will identify transcriptome-wide mRNA targets of the target RBPs and will investigate individual mRNA-RBPs target pairs on a molecular level to reveal their mode of action.By achieving these aims, we will increase our knowledge on how candidate RBPs orchestrate the balance between self-renewal, proliferation and differentiation in normal and malignant hematopoiesis. Moreover, by understanding how their deregulation drives leukemogenesis, we will identify new proteins and/or pathways, which can be targeted in the treatment in hematologic malignancies, with the ultimate goal to design novel treatment strategies in high risk AML and ALL.
DFG Programme
Research Units
