Project Term
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Project Summary
In-frame mutations affecting the basic leucine zipper (bZIP) domain of C/EBPα characterize a distinct subset of acute myeloid leukemia with relatively favorable prognosis, though five-year overall survival remains roughly 60%. Using new mouse models, this project will identify targets of endogenous bZIP–mutated C/EBPα. We will test whether modulating mutant-specific targets alters disease course in mouse models and in patient-derived xenografts, thereby nominating new approaches to therapy.
Lay Abstract
Despite being associated with "favorable" prognosis, around one-third of patients who have acute myeloid leukemia (AML) with mutations in the gene CEBPA do not survive beyond five years, underscoring the need for better treatment strategies.
I am working to improve our understanding of the molecular events that transform healthy bone marrow cells into this subset of AML. Mutations in CEBPA affect the transcription factor protein it encodes, which in turn regulates the expression of other genes in developing blood cells. Previous studies have faced limitations in accurately simulating the effect of CEBPA mutations due to technical constraints, but I have developed new genetically modified mice, established a human patient-derived xenograft (transplanting a human leukemia sample into mice), and refined experimental techniques in order to model this disease more faithfully.
These tools enable deeper investigation of the DNA-binding activity of mutant protein across the genome as well as its protein interaction partners, and they will help us to better understand how gene regulation is disrupted during early stages of blood cell development in ways that lead to cancer. By continuing to build on early evidence we have collected challenging some prevailing ideas in this area, my goal is to find weaknesses unique to CEBPA-mutated AML. I will also create experimental systems that model additional co-mutations found in patients as their disease evolves over time in order to study how these mutations can amplify or restrict each other's effects.
Success of this project will hinge on demonstrating specific genes or pathways that, if modified, can either prevent progression to leukemia or stop its growth. Next steps would then include testing chemical compounds that affect those targets in the mouse and patient-derived models assembled for this project. Progress along these lines will be crucial for patients who do not achieve remission or who experience relapse after traditional chemotherapy.
Program
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