Friday, May 9, 2025
5/9/2025
Targeted therapy for t(8;21)+ AML - PROJECT SUMMARY Acute myeloid leukemia (AML) remains one of the most difficult-to-treat malignancies, with most patients receiving decades old chemotherapy agents and experiencing relapse and/or refractory disease. Finally, targeted therapies are making their way into the treatment of AML, and we are focused on developing a targeted therapy for t(8;21) AML. The most common translocation in AML, t(8;21), generates a chimeric transcription factor (TF), AML1-ETO (AE), that is oncogenic and possesses both transcriptional activating and repressing effects on its target genes. AE dominantly inhibits AML1 (aka RUNX1) and has many functional attributes not present in the wild type AML1 or ETO proteins. We linked the ability of AE to promote hematopoietic stem cell (HSC) self-renewal to its ability to activate gene expression, and its ability to block myeloid differentiation to its ability to repress gene expression. The p300 dependent acetylation of AE on lysine 43 (K43)1 enables AE to interact with the bromodomain of TAF12, leading to activation of gene expression, enhanced stem cell self-renewal and the proliferation of AE- driven AML. Given the inherent difficulties of targeting AE directly, we have been targeting its required co-factors with p300/CBP inhibitors and Taf1 bromodomain inhibitors. More recently we have implicated the ETV6 repressor protein and the chromatin-associated signaling molecule Rac1 in gene repression by AE. We hypothesize that targeting gene activation, gene repression and the signaling pathways (such as AKT) activated by AE will lead to the development of effective targeted therapy for AE+ AML. To test this hypothesis, we propose the following specific aims: Aim 1. Determine how the interaction of AE with TAF1 affects AE-mediated gene activation, HSPC biology, and AE-driven leukemogenesis. Aim 2. Determine how Rac1/ETV6 functions in AE-mediated gene repression and leukemogenesis. Aim 3. Determine how the targeting of AE-driven gene activation and gene repression, alone or in combination with the targeting of signaling pathways that are activated by AE or Rac1, affect the growth of AE+ AML. We will focus on the AE-TAF1 complex that promotes gene activation, HSPC self-renewal and leukemogenesis, and on the regulation of ETV6 and ETV6/AE-bound enhancer function by Rac1 that affects the ability of AE to impair differentiation and drive leukemia. We will also test treatment strategies using inhibitors for p300/CBP, TAF1, Rac1 and ETV6 in the initiation and maintenance of AE+ AML. The studies detailed in this proposal will define critical molecular events that underlie AE-driven leukemia, and hasten the development of novel, targeted therapeutic strategies.
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