Mechanisms of Inducing differentiation in CBFA2T3-GLIS2 positive AML
Rachel Mersfelder
Dana-Farber Cancer Institute
Project Term: July 1, 2024 - June 30, 2025
AMKL is a rare leukemia that largely affects infants and toddlers. Of the various subtypes of this disease, CBAF2T3-GLIS2 positive AMKL has proven particularly difficult to treat with traditional cytotoxic chemotherapies and bone marrow transplantation with dismal outcomes. The objective of this study is to investigate protein dependencies in CBAFT2T3-GLIS2 fusion positive AMKL to identify new, and desperately needed, drug targets.
Acute megalokaryoblastic leukemia (AMKL) is a rare and often highly aggressive subtype of acute myeloid leukemia (AML) that largely affects infants and toddlers. Therapy outcomes have been shown to be linked to genetic subtypes, with the worst prognosis for patients harboring the CBFA2T3-GLIS2 fusion. Despite intense chemotherapy and bone marrow transplantation, the 5-year overall survival rates for these patients is 15-20%.
Given the need for improved therapies for this disease, our lab aims to better understand the specific biology of the CBFA2T3-GLIS2 fusion in order to use this knowledge to develop more targeted, and hopefully more effective, therapies. Using CRISPR screening technology, we have identified genes that are necessary for the survival of CBFA2T3-GLIS2 positive AMKL cells. Our project aims to further investigate these genes, the biology they mediate, and how they interface with the fusion oncoprotein to sustain leukemia. By doing so, we hope to elucidate a druggable target and improve survival for children afflicted by this disease.