CRISPR Identifies ZNF740 as Key to Venetoclax Sensitivity

The study highlights ZNF740’s regulation of the pro-apoptotic protein NOXA, which influences the stability of MCL-1, a key factor in venetoclax resistance. Venetoclax is an oral medication that blocks BCL-2 - a protein that helps cancer cells survive by preventing programmed cell death (apoptosis) - thereby restoring the apoptotic process and allowing cancer cells to die.

In this study, researchers employed a CRISPR knockout screen to investigate the functional significance of genes associated with venetoclax sensitivity in AML. Targeting around 1400 genes, they discovered that ZNF740 is a critical regulator, with its depletion leading to venetoclax resistance and its overexpression enhancing drug sensitivity.

The CRISPR screen revealed that ZNF740 influences the expression of NOXA, a gene that destabilises the MCL-1 protein, thereby promoting cell death in response to venetoclax. Loss of ZNF740 results in reduced NOXA levels, increased MCL-1 stability, and subsequent resistance to venetoclax.

By restoring NOXA expression in ZNF740-deficient cells, researchers were able to re-sensitise AML cells to venetoclax. Furthermore, a combined approach targeting both MCL-1 and BCL-2 effectively overcame resistance in ZNF740-deficient AML in both cellular and animal models.

Lixia Zhang and Rui Lu from the University of Alabama at Birmingham led the study, and it was published in Cell Death and Disease on 27 August 2024.