This proposal describes a 5-year career development program designed to support an academic, physician- scientist career. The proposed research project will capitalize on the expertise and resources available at Washington University in St. Louis, which has a long tradition of developing physician-scientists. Dr. Timothy Ley, an expert in myeloid development and cancer genomics and a recipient of the American Society of Hematology Mentor Award, will serve as the research mentor. The ultimate goal of the candidate is to be an independent investigator in an academic medical center, studying normal and malignant hematopoiesis and taking care of patients with hematologic diseases. The experiments outlined in this application aim to clarify the role of wild type and mutant WT1 in Acute myeloid leukemia (AML) progression, with the goal to create new therapeutic approaches for this disease. Wilms tumor 1 (WT1) is a zinc-finger family transcription factor that is highly expressed in AML cells compared to normal hematopoietic progenitor cells, consistent with a possible role in promoting AML development and leading to considerable clinical interest in WT1 as a therapeutic target. Paradoxically, loss-of-function mutations in WT1 are also found in a subset of AML cases, raising the possibility that WT1 may promote or inhibit development of leukemia depending on the molecular context. Our lab recently performed preliminary studies suggesting that when co-occurring with the PML-RARA fusion, WT1 inhibits leukemic progression and self-renewal in a mouse model, suggesting that in this setting WT1 may prevent or delay leukemic progression. To reconcile the seemingly contradictory role of WT1 in AML progression we developed the following hypothesis to be tested in this proposal: WT1 expression is triggered in hematopoietic progenitors as a defensive response to AML-associated driver mutations. While fully transformed AML has developed means to overcome this inhibition, subsequent loss-of function mutations in WT1 provide a growth advantage to mutant subclones. Consistent with this hypothesis, we recently found that WT1 mRNA is induced 10-fold in CD34+ cells that have been transduced with several canonical AML-associated fusion genes. In this proposal, we will extend these observations to test whether overexpression or loss-of-function of WT1 can cooperate with these AML-associated mutations in mouse and human systems.
Wilms tumor 1 (WT1) is a zinc-finger family transcription factor that is highly expressed in the majority of cases of AML. Interestingly, loss-of-function mutations also occur in a subset of cases, and the mechanisms by which WT1 may promote or inhibit AML development remain poorly understood. In the proposed studies we will test whether WT1 overexpression or mutation cooperates with a variety of canonical AML-associated mutations. Through these experiments we will develop a system for unraveling downstream mechanisms by which WT1 may act in leukemia cells.
|Christopher, Matthew J; Petti, Allegra A; Rettig, Michael P et al. (2018) Immune Escape of Relapsed AML Cells after Allogeneic Transplantation. N Engl J Med 379:2330-2341|