Understand Non-canonical RAS Signaling in Clonal Hematopoietic Disorders

PROJECT SUMMARY AND ABSTRACT CANDIDATE: Dr. Sisi Chen is a postdoctoral research associate in the Human Oncology and Pathogenesis Program (HOPP) at the Memorial Sloan Kettering Cancer Center (MSKCC). Her long-term career goal is to become an independent investigator, studying the role of critical regulators of hematopoiesis and identifying

oncogenic drivers of myeloid neoplasms. Under the mentorship of Dr. Omar Abdel-Wahab, a leader in the field of functional genomics of hematopoietic malignancies, Dr. Chen has outlined a focused five-year career training plan that will (1) bolster scientific scope and experimental skillsets; (2) improve presentation and

communication skills; (3) enhance leadership potential and networking; and (4) prepare for mentoring future trainees. She has established an advisory committee that will provide robust mentoring for her research and career development. Dr. Chen has a highly exciting project that is sufficiently distinct from her mentor's research,

and that will form a solid platform to establish her own research group by the end of the K99 Award period. RESEARCH: Recent studies discovered LZTR1 as a substrate adaptor for a CUL3 ubiquitin ligase complex responsible for ubiquitin-mediated degradation of RAS GTPases. In parallel, aberrant LZTR1 splicing and

mutations in LZTR1 as well as the LZTR1 substrate, a non-canonical RAS GTPase RIT1, were identified in clonal hematopoiesis and myeloid neoplasms. The overarching goal of this proposal is to determine the role of non-canonical RAS signaling regulation pathway in normal and malignant hematopoiesis through

a combination of murine modeling, unbiased multi-omics, and focused biochemical studies. Our preliminary data shows that impaired non-canonical RAS protein proteolysis drives clonal hematopoietic expansion, leading to the hypothesis that non-canonical RAS GTPases and their regulator represent important

molecular determinants in normal and neoplastic hematopoietic stem and progenitor cells. The Specific Aims are: (1) Comprehensively Identify novel substrates for LZTR1-mediated proteolysis in hematopoietic cells; (2) Determine the role of non-canonical RAS GTPase MRAS on hematopoietic stem cell self-renewal and

differentiation; and (3) Identify the mechanisms by which mutant RIT1 transforms hematopoietic stem cells. ENVIRONMENT: MSKCC provides trainees an exceptional academic research environment with a strong commitment to support their career development. The Abdel-Wahab laboratory is in the HOPP program at

MSKCC, a department that specializes in mechanism-based research to advance clinical translation. The primary mentor Dr. Abdel-Wahab is the Director of the MSK Center for Hematologic Malignancies. These

affiliations provide a rich set of collaboratives, technical and scientific resources for the current proposal. Dr. Sisi Chen is therefore positioned at the best institutional environment to execute the research outlined here, as well as to receive outstanding career development training to obtain an independent tenure-track faculty position.