Venetoclax (VEN), a conventional treatment for chronic lymphocytic leukemia (CLL), suppresses the prosurvival protein BCL2 to cause apoptosis and induces high rates of full remission and prolonged progression-free survival in relapsed CLL, but eventually loses its effectiveness. A variety of subclonal genetic alterations connected to VEN resistance have been identified. 

For a study, researchers used single-cell short- and long-read RNA-sequencing to show the hitherto underappreciated scope of genetic and epigenetic alterations underlying acquired VEN resistance in order to completely understand clinical resistance to VEN. These had several layers. One layer consisted of modifications to the prosurvival members of the BCL2 family of apoptosis regulators. It included previously known BCL2 mutations and MCL1 gene amplifications, although it varied across and among distinct patient leukemias. With the exception of a few isolated examples involving subclonal deletions of BAX or NOXA, changes in proapoptotic genes are very rare. The ubiquitous overexpression of the MCL1 gene was much more noticeable. 

During VEN treatment, circulating cells continued to exhibit emergent NF-κB (nuclear factor kappa B) activation, which was the driving force behind this. They found that MCL1 could be NF-κB’s direct transcriptional target. Following the termination of VEN, both the transition to alternate prosurvival factors and NF-κB activation substantially disappear. 

The research demonstrated the degree to which CLL cells are flexible in their resistance to VEN-induced apoptosis. In addition to providing a precise biological explanation for the strategy of discontinuing VEN after a maximum response is obtained rather than sustaining long-term selective pressure with the medication, thee findings also suggested novel ways to overcome VEN resistance.

Reference: ashpublications.org/blood/article/140/20/2127/485591/Single-cell-multiomics-reveal-the-scale-of