Abstract 5628: Aberrant 3'UTR processing regulates a tumor suppressor network in AML

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Differentiation blockade is a hallmark of acute myeloid leukemia (AML). While inactivating mutations in tumor suppressor genes (TSGs) have been well-studied, non-genetic mechanisms that impair TSGs to promote myeloid differentiation and influence drug response remain poorly understood. In this study, we performed genome-wide loss-of-function CRISPR/Cas9 screens to identify suppressors of myeloid differentiation. These screens converged on the zinc finger transcriptional repressor, ZBTB7A whose ablation restricted myeloid maturation and promoted a dysregulated inflammatory state to protect leukemic cells from undergoing differentiation. Moreover, genetic deletion of ZBTB7A or its paralog, ZBTB7B impeded leukemia differentiation and conferred resistance to differentiation-inducing agents. Mechanistically, we found that leukemia cells hijack 3’UTR processes to reduce mRNA expression of the tumor suppressor gene paralogs ZBTB7A and ZBTB7B. These findings provide a molecular framework of altered 3’UTR regulation that orchestrate a tumor suppressive function and promote resistance to AML differentiation-based therapies. Citation Format: Eric Wang, Cuijuan Han, Alexander Calderon, Abimbo Lawal, Sakthi Harini Rajendran, Sadik Karma, Nidhi Hariramani, Iannis Aifantis, Aristotelis Tsirigos. Aberrant 3'UTR processing regulates a tumor suppressor network in AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5628.