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Probing Acetyl-Lysine Writer and Reader Function in Acute Myeloid Leukemia
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Probing Acetyl-Lysine Writer and Reader Function in Acute Myeloid Leukemia
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Dissertation
Probing Acetyl-Lysine Writer and Reader Function in Acute Myeloid Leukemia
2023
Overview
Transcriptional coregulatory proteins that mediate transcription factor signaling and modify the chromatin landscape are frequently implicated in oncogenesis and represent one of the fastest-growing target classes in small-molecule drug discovery. Small molecule inhibitors of these targets represent potential starting points for therapeutics as well as valuable tools to (1) dissect the roles of their target proteins in controlling oncogenic transcriptional programs and (2) uncover gene-drug interactions that modulate drug sensitivity. Here we discover and apply new chemical matter to probe the functions of the acetyl-lysine binding YEATS domains of ENL/AF9 in acute myeloid leukemia (AML). In doing so we find that YEATS domain inhibition displaces ENL from chromatin and specifically disrupts the transcription of ENL-bound leukemogenic genes. This work further confirms ENL as an attractive therapeutic target in AML and crucially establishes that pharmacological YEATS domain inhibition can disrupt pathogenic ENL-driven transcription. Furthermore, we use recently discovered inhibitors of the histone acetyltransferases (HATs) of CBP/p300 to understand the role of the enzymatic function of these proteins in controlling tumorigenic transcription in AML. Despite large differences in primary sensitivity to CBP/p300 HAT inhibition we find that the acute transcriptional effects of CBP/p300 HAT inhibition are largely the same in both sensitive and insensitive cell lines and characterized by vast histone hypoacetylation and specific loss of transcription of enhancer-controlled genes. We also use multiple genetic strategies to uncover cellular pathways that affect sensitivity to CBP/p300 HAT inhibitors. These experiments converge on the coenzyme A (CoA) biosynthetic pathway as a major modulator of HAT inhibitor sensitivity, where alterations that ultimately increase acetyl-CoA production lead to disruption of target engagement and resistance to HAT inhibitors. In all, this work provides new chemical tools to probe the function of the ENL/AF9 YEATS domains in cellular systems, identifies CBP/p300 HAT inhibition as a potential therapeutic strategy in AML, elucidates the mechanisms by which CBP/p300 HAT inhibition disrupts oncogenic transcription, and uncovers an important mechanism of resistance to this emerging class of drugs.
