BCL2 Protein Progressively Declines during Robust CLL Clonal Expansion: Potential Impact on Venetoclax Clinical Efficacy and Insights on Mechanism

• DOI: 10.3390/lymphatics2020005
• Publication Date: 2024-03-28T17:20:53Z
• Authors: Hyunjoo Lee; Shabirul Haque; Rashmi Gupta; Jonathan E. Kolitz; Steven L. Allen; Kanti Rai; Nicholas Chiorazzi; Patricia K. A. Mo...
• Keywords: Venetoclax

CLL B cells express elevated pro-survival BCL2, and its selective inhibitor, venetoclax, significantly reduces leukemic cell load, leading to clinical remission. Nonetheless, relapses occur. This study evaluates the hypothesis that progressively diminished BCL2 protein in cycling within patient lymph node niches contributes relapse. Using CFSE-labeled, purified populations known respond with vigorous d6 cultures stimulated TLR9-activating ODN (oligodeoxynucleotide) + IL15, we show declines during consecutive divisions. In contrast, MCL1 survivin are maintained/slightly cycling. Delayed pulsing of quiescent activated inhibitors or revealed targeting noncycling populations, respectively, raising implications for therapy. To address BCL2-repressive miRs (