Monday, May 12, 2025
5/12/2025
The role of SRCAP in therapy related clonal hematopoiesis - PROJECT SUMMARY Therapy-related myeloid neoplasms (t-MN) arise following the administration of chemotherapy or radiation and are a devastating complication of treatment given to cure cancers and treat other inflammatory conditions. There remains a gap in our understanding of how t-MNs arise and, thus, how we can better identify patients at the highest risk of developing them and prevent their development. Many t-MNs evolve from pre-existing clonal hematopoiesis (CH), a pre-malignant state, that develops or expands in the setting of cytotoxic therapy exposure. The long-term goal is to understand better the processes that drive clonal selection in the hematopoietic system, thus the development of CH and evolution to t-MN. The overall objective in this application is to understand how mutations in SRCAP, a gene recurrently mutated in CH among therapy-exposed patients (t-CH), promotes hematopoietic cell expansion and pre-malignancy. SRCAP encodes for a conserved ATPase that deposits the histone variant H2AZ on chromatin and plays essential roles in the epigenetic regulation of transcription and DNA repair. The central hypothesis is that loss of SRCAP dysregulates the DNA damage response (DDR) by altering deposition of H2AZ at sites of DNA double-strand breaks and at the promoters of genes involved in the DDR and thus confers resistance to cytotoxic agents leading to the clonal outgrowth of mutant hematopoietic stem and progenitor cells. Guided by robust preliminary data and the development of a novel conditional knockout mouse model, this hypothesis will be tested by pursuing three specific aims: 1) Study the role of SRCAP in hematopoiesis during normal and stressed states using a novel conditional mouse model; 2) Determine how SRCAP regulates the response to DNA damage; 3) Determine how Srcap mutations influence the evolution and clonal expansion of t-CH. In the first aim, a novel conditional Srcap knockout mouse has been generated and will be used to study the role of SRCAP during normal hematopoiesis and during cytotoxic therapy-induced stress. This mouse is currently in the lab and available for use. In the second aim, the role of SRCAP in regulating the response to cytotoxic therapies and the DNA damage response pathway in both human and mouse cell lines will be evaluated. Finally, in aim 3, the evolution of t-CH will be assessed by generating mice with mutations in Srcap and other genes recurrently mutated in CH and myelodysplasia to evaluate effects on hematopoiesis. The approach is innovative because it utilizes a novel conditional mouse model and provides the opportunity to study both the regulation of the DDR and epigenetic regulation of hematopoietic stem and progenitor cells, two processes known to be essential mediators of disease in CH and myeloid malignancies. The proposed research is significant because it will expand our understanding of how hematopoietic cells evolve in the setting of cytotoxic therapy and the role of SRCAP in normal and stressed hematopoiesis. Ultimately, this knowledge may provide new opportunities to develop strategies for the early detection and prevention of t-MNs.
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