Project Details
Projekt
Discovery and characterization of EZH2-regulated RBP feed-forward mechanisms controlling cellular transformation
Applicant
Professor Dr. Dirk Heckl
Subject Area
Hematology, Oncology
General Genetics and Functional Genome Biology
General Genetics and Functional Genome Biology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 468534282
Acute myeloid leukemia is the most fatal hematopoietic malignancy in Germany with little improvements in age-corrected mortality. The treatment regimens are composed of cytotoxic chemotherapy in quiet static regimens with little variation, and bone marrow transplantation for recurrent/refractory disease and high-risk groups. More targeted –and less toxic- regimens would be highly desirable. Towards this goal, understanding the origin and function of AML, the alterations causing malignant conversion and the dependencies of the disease initiating cells are crucial milestones. However, neither the genetic nor the transcriptomic analyses of AML was able to resolve all mechanisms of transformation and post-transcriptional or post-translational effects are of high promise to open new venues to understand and treat cancer. Key players of these processes are RNA-binding-proteins (RBPs), which can modulate RNA-abundance and its translation into protein. In prior studies we have studied the epigenetic regulator EZH2 and its role in cancer. These studies unraveld the negative regulation of a plethora of RBPs by EZH2 and their upregulation upon loss of EZH2 during carcinogenesis. We thus hypothesize that finetuning of the transcriptome through EZH2 mediated RBP control is a major feed-forward loop regulating cellular differentiation, regeneration and maintenance of the benign cell state. Understanding these regulatory functions of the EZH2-RBP-axis, isolation of the major RBP mediators, and their characterization in health and disease will not only provide insights into the orchestration of cell fate decisions but may also equip cancer treatment with new levers. Based on our preliminary data, we identified a list of EZH2-regulated RBPs with strong (>10-fold) deregulation upon EZH2-loss. In this study, we will identify the cancer-relevant RBPs from our candidate list by applying gain-of-function (increasing RBP levels) and loss of function (depleting RBPs) in healthy and malignant cells (WP1). With proven expertise in cellular and molecular characterization, cellular and molecular function of the functionally relevant will be defined both in healthy and malignant cells (WP2). These data will enable us to develop and test targeted, RBP-centered therapeutic approaches and translate our findings to pre-clinical models (WP3). Uncovering the proposed EZH2-RBP transcriptome reshaping feed-forward loop and making it exploitable for targeted treatment may thereby become the stepstone for advanced cancer treatment and cellular regeneration.
DFG Programme
Research Units
