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Jennifer R. Brown, MD, PhD

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Genetic Underpinnings of CLL Relapse During Venetoclax Treatment

By: Jenna Carter, PhD
Posted: Tuesday, August 30, 2022

Use of venetoclax to inhibit the protein BCL2 and induce apoptosis is a standard therapy for chronic lymphocytic leukemia (CLL). Furthermore, the agent has been shown to deliver high complete remission rates and prolonged progression-free survival in relapsed cases; however, there is an eventual loss of efficacy. A recent article published in Blood highlighted the genetic underpinnings of venetoclax resistance to circumvent this issue. Professor David Ching Siang Huang, of The Walter & Eliza Hall Institute of Medical Research, Parkville, Australia, and colleagues combined single-cell short- and long-read RNA sequencing to reveal the scale of genetic and epigenetic changes underlying acquired resistance. They found the emergence of venetoclax relapse in CLL consisted of high NF-κB and MCL1 expression, as well as a second layer of genetic and epigenetic changes that center around manipulations in the core apoptotic machinery.

“Our single-cell multiomics analyses reveal that the emergence of venetoclax relapse in CLL is highly complex, with multiple coexisting changes present,” stated Dr. Huang and colleagues.

Peripheral blood samples were collected from patients whose CLL progressed after 30 to 84 months of continuous venetoclax monotherapy (n = 13); they were compared with screening samples (n = 7) collected from the same patients prior to treatment with venetoclax. Single-cell RNA sequencing, full transcriptome, and rapid capture hybridization sequencing were performed.

Overall findings revealed upregulation of MCL1 (a prosurvival gene), which appeared to be driven by emergent NF-κB activation persistent in circulating cells during venetoclax therapy. To assess a causal link between NF-κB activation and MCL1 upregulation, the investigators performed a CHIP-seq assay and found that MCL1 was a direct transcriptional target of NF-κB. Additionally, upon discontinuation of venetoclax, NF-κB activation was largely dissipated. Additional findings revealed increased expression of prosurvival relatives of BCL2 that are not targeted by venetoclax (MCL1, BCL2A1, BCLxL)—they were typically subclonal; however, they also seemed to contribute to the resistant population. 

Disclosure: The study authors reported no conflicts of interest.


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