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Michael Drazer, M.D.
Elucidating leukemogenic mechanisms in hereditary hematopoietic malignancies

Michael Drazer, M.D.

University of Chicago

2020 Funding recipient

Elucidating leukemogenic mechanisms in hereditary hematopoietic malignancies

EvansMDS Young Investigator Award

PROJECT SUMMARY

Hereditary hematopoietic malignancies (HHMs) caused by germline mutations are recognized increasingly, but mechanisms driving HHMs are poorly understood, and no HHM-specific therapies exist. The objective of my Evans YIA proposal is to systematically elucidate a mechanistic link among the established HHM syndromes, with a particular focus on HHMs driven by germline mutations in ANKRD26 or RUNX1.

Most RUNX1 carriers have evidence of clonal hematopoiesis (CH), a process by which hematopoietic stem and progenitor cells acquire somatic driver mutations that convey a growth/survival advantage, proliferate, and potentially transform into hematopoietic malignancies such as myelodysplastic syndrome or acute leukemia (MDS/AL). However, it is not known if a similar phenomenon occurs among individuals with other HHM associated mutations. My preliminary data demonstrate that CH occurs in a unique pattern among individuals with germline mutations in ANKRD26, DDX41, ETV6, or RUNX1. Specifically, a shared set of CH mutations occur in ANKRD26 or RUNX1 carriers. These “high-risk” CH mutations are also seen in ANKRD26 or RUNX1 germline mutation carriers who develop overt myeloid malignancies. These CH mutations are not observed in DDX41 or ETV6 carriers, suggesting that distinct mechanisms of leukemogenesis occur in individuals with ANKRD26 or RUNX1 germline mutations.

My central hypothesis is that shared therapeutic vulnerabilities exist among myeloid malignancies stemming from germline mutations in ANKRD26 or RUNX1 relative to germline DDX41 or ETV6 mutations. I hypothesize that I may utilize my panel of patient-derived induced pluripotent stem cells (iPSCs) to systematically model the effects of HHM and CH mutations on hematopoiesis, identify mechanisms of leukemogenesis, and develop novel therapies specific to HHMs.