Venetoclax, a BCL2 inhibitor, has been authorized to treat several hematological cancers. For a study, researchers investigated if epigenetic processes may be involved in venetoclax resistance as there is, no shared genetic mutation-producing resistance to the drug in chronic lymphocytic leukemia (CLL) and B-cell lymphoma. 

Due to this, they used whole-exome sequencing, methylation DNA immunoprecipitation sequencing, and genome-wide CRISPR/CRISPR-associated protein 9 screening to look into venetoclax resistance in aggressive lymphoma and high-risk CLL patients. They discovered a regulatory CpG island in the PUMA promoter that, in response to venetoclax therapy, is methylated, facilitating the downregulation of PUMA at the transcript and protein levels. Methyltransferase inhibition can restore PUMA expression and susceptibility to venetoclax. They showed that the loss of PUMA causes a metabolic reprogramming that is similar to the metabolic phenotype found with venetoclax resistance, with increased oxidative phosphorylation and adenosine triphosphate generation. 

BAX is necessary for sensitivity to venetoclax and MCL1 inhibition, despite the fact that PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not observed in CLL patients following chemotherapy-resistance. They characterized BAX-mediated apoptosis as being necessary for drug resistance but not for disease progression of CLL into aggressive diffuse large B-cell lymphoma in vivo because they discovered the loss of BAX in Richter’s syndrome patients after venetoclax failure. A compound screen identified TRAIL-mediated apoptosis as a target to overcome BAX deficiency. In addition, venetoclax resistance was overcome by the elimination of venetoclax-resistant lymphoma cells using antibodies or CAR T cells.

Reference: ashpublications.org/blood/article/140/20/2113/485569/Deregulation-and-epigenetic-modification-of-BCL2