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September 10, 2025

Abstract P83: The Change of Partners in Apoptosis Induction in the CLL Cells

Key Points

Apoptosis induction was significantly faster and more robust with venetoclax compared to Mcl-1 targeting.
The combination of fadraciclib and venetoclax led to a synergistic effect in inducing cell death among CLL cells.
Significant binding interactions were observed, with BAK predominantly partnering with Mcl-1, while BAX was associated with Bcl-2.
Understanding these interactions may inform future therapies targeting key pro-survival proteins in CLL.

Abstract

Abstract Chronic lymphocytic leukemia (CLL) is characterized by the over-expression of the Bcl-2 family anti-apoptotic proteins that sustain the leukemia cells survival. Therapeutic agents that either deplete Mcl-1 (such as fadraciclib, a CDK9 inhibitor) or antagonize Bcl-2 (venetoclax) can both induce apoptosis in the primary CLL cells, indicating the dependence of the CLL viability on these pro-survival proteins. However, diminishing Mcl-1 triggered a relatively slow cell death, that gradually increase over the 24 h period, compared to a quick and robust apoptosis induced by venetoclax, that peaked within a few hours. Their combination led to a deeper and synergistic cell killing. To understand the mechanism behind the different dynamics of action, we performed a series analysis such as flow cytometry and immuno-precipitation to understand the interplay of Bcl-2 family proteins in CLL cells incubated with fadraciclib, venetoclax or the combination. Our results showed that the major partner of Mcl-1 is BAK in the CLL cells, and Bcl-2 binds mostly to BAX. The freed BAK from Mcl-1 form hetero-complex with BAX, shown by the co-immunoprecipitation analysis. Although Bcl-2 does not bind directly to BAK, BAK was quickly activated by venetoclax. These data indicated that the activated BAK and BAX may recruit and potentiate each other to initiate apoptosis. Due to the high expression of Bcl-2 and BAX, releasing BAX from Bcl-2 quickly activated sufficient quantities of BAX to initiate apoptosis. On the contrary, Mcl-1 and BAK were expressed at a level of only one-tenth of Bcl-2. Releasing of BAK from Mcl-1 gradually sequester and activate BAX to reach the threshold for apoptosis induction. The combination released both BAX and BAX to synergistically induce apoptosis. Defining these molecular interactions is important to obtain a deeper understand of drug action and helpful for the design of mechanism-based therapy and combinations for CLL. Citation Format: Rong Chen, Ping Xiong, Yuling Chen, William Wierda and William Plunkett. The Change of Partners in Apoptosis Induction in the CLL Cells abstract. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85 (15Suppl): Abstract nr P83.

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