2. Academic Validation
  3. CRISPR screen of venetoclax response-associated genes identifies transcription factor ZNF740 as a key functional regulator

CRISPR screen of venetoclax response-associated genes identifies transcription factor ZNF740 as a key functional regulator

  • Cell Death Dis. 2024 Aug 27;15(8):627. doi: 10.1038/s41419-024-06995-x.
Lixia Zhang 1 2 3,  Xinyue Zhou 1 2,  Sajesan Aryal 1 2,  Virginia Veasey 1 2,  Pengcheng Zhang 1 2,  Fu Jun Li 1 2,  Yu Luan 4 5,  Ravi Bhatia 1 2,  Yang Zhou 6,  Rui Lu 7 8
Affiliations

Affiliations

  • 1 Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA.
  • 2 O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA.
  • 3 Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 4 Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA.
  • 5 Greehey Children's Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX, USA.
  • 6 Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 7 Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA. ruilu1@uabmc.edu.
  • 8 O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA. ruilu1@uabmc.edu.
PMID: 39191721 DOI: 10.1038/s41419-024-06995-x
Abstract

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 leads to increased resistance to ventoclax, while its overexpression enhances sensitivity to the drug. Mechanistically, our integrative transcriptomic and genomic analysis identifies NOXA as a direct target of ZNF740, which negatively regulates Mcl-1 protein stability. Loss of ZNF740 downregulates NOXA and increases the steady state protein levels of Mcl-1 in AML cells. Restoring NOXA expression in ZNF740-depleted cells re-sensitizes AML cells to venetoclax treatment. Furthermore, we demonstrated that dual targeting of Mcl-1 and Bcl-2 effectively treats ZNF740-deficient AML in vivo. Together, our work systematically elucidates the causal relationship between venetoclax response signature genes and establishes ZNF740 as a novel transcription factor regulating venetoclax sensitivity.

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