Profiling by BH3 mimetics that target either Bcl-, Bcl-XL or Mcl-1, was performed in CLL cells
fully resistant to venetoclax due to CD40 stimulation. This model induces simultaneous
expression of Bcl-XL, Mcl-1 and Bfl-1, and resembles the LN situation in that respect4. Several
dual or triple combinations of BH3 mimetics were highly synergistic in restoring killing of CLL
cells, with the effect of Bcl-XL being the strongest in terms of EC50. Lastly, we demonstrated
that pro-apoptotic Bim interacts with anti-apoptotic Bcl-2 members in a sequential manner:
Bcl-2>Bcl-XL>Mcl-1>Bfl-1.
Conclusions: The data indicate that Bcl-XL is more important in venetoclax resistance than
Mcl-1 when both are present. Combined, our data provide biological rationale for potential
synergy between ibrutinib and venetoclax in clinical application.
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