biostudies-literatureZhang LAmerican Cancer SocietyThe Mark Foundation for Cancer ResearchAmerican Cancer Society (American Cancer Society, Inc.)NCI NIH HHSAmerican Society of HematologyU.S. Department of Health & Human Services | National Institutes of Health (NIH)Gabrielle’s Angel Foundation for Cancer ResearchU.S. Department of Health & Human Services | National Institutes of Health627https://www.ebi.ac.uk/biostudies/studies/S-EPMC11350041biostudies-literatureUnknown15(8)BCL-2 inhibitors such as venetoclax offer therapeutic promise in acute myeloid leukemia (AML) and other cancers, but drug resistance poses a significant challenge. It is crucial to understand the mechanisms that regulate venetoclax response. While correlative studies have identified numerous genes linked to venetoclax sensitivity, their direct impact on the drug response remains unclear. In this study, we targeted around 1400 genes upregulated in venetoclax-sensitive primary AML samples and carried out a CRISPR knockout screen to evaluate their direct effects on venetoclax response. Our screen identified the transcription factor ZNF740 as a critical regulator, with its expression consistently predicting venetoclax sensitivity across subtypes of the FAB classification. ZNF740 depletion leadCell death & diseaseCRISPR screen of venetoclax response-associated genes identifies transcription factor ZNF740 as a key functional regulator.PMC11350041R01 CA259480RSG-22-036-01-DMCCA259480Luan YAryal SLi FJZhang LBhatia RZhou YZhou XVeasey VZhang PLu RfalseCRISPR screen of venetoclax response-associated genes identifies transcription factor ZNF740 as a key functional regulator.BCL-2 inhibitors such as venetoclax offer therapeutic promise in acute myeloid leukemia (AML) and other cancers, but drug resistance poses a significant challenge. It is crucial to understand the mechanisms that regulate venetoclax response. While correlative studies have identified numerous genes linked to venetoclax sensitivity, their direct impact on the drug response remains unclear. In this study, we targeted around 1400 genes upregulated in venetoclax-sensitive primary AML samples and carried out a CRISPR knockout screen to evaluate their direct effects on venetoclax response. Our screen identified the transcription factor ZNF740 as a critical regulator, with its expression consistently predicting venetoclax sensitivity across subtypes of the FAB classification. ZNF740 depletion lead2024-01-01T00:00:00Z2024 Aug2026-05-04T06:49:34.362Z2025-04-06T16:44:23.674ZS-EPMC113500413919172110.1038/s41419-024-06995-x