Regulation of Bcl-XL by non-canonical NF-κB in the context of CD40-induced drug resistance in CLL

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Haselager, Marco and Thijssen, Rachel and West, Christopher and Young, Louise and Van Kampen, Roel and Willmore, Elaine and Mackay, Simon and Kater, Arnon and Eldering, Eric (2021) Regulation of Bcl-XL by non-canonical NF-κB in the context of CD40-induced drug resistance in CLL. Cell Death and Differentiation, 28 (5). pp. 1658-1668. ISSN 1350-9047 (https://doi.org/10.1038/s41418-020-00692-w)

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Abstract

In chronic lymphocytic leukemia (CLL), the lymph node (LN) microenvironment delivers critical survival signals by inducing the expression of anti-apoptotic Bcl-2 members Bcl-XL, Bfl-1, and Mcl-1, resulting in apoptosis blockade. We determined previously that resistance against various drugs, among which is the clinically applied BH3 mimetic venetoclax, is dominated by upregulation of the anti-apoptotic regulator Bcl-XL. Direct clinical targeting of Bcl-XL by, e.g., Navitoclax is however not desirable due to induction of thrombocytopenia. Since the actual regulation of Bcl-XL in CLL in the context of the LN microenvironment is not well elucidated, we investigated various candidate LN signals to drive Bcl-XL expression. We found a dominance for NF-κB signaling upon CD40 stimulation, which results in activation of both the canonical and non-canonical NF-κB signaling pathways. We demonstrate that expression of Bcl-XL is first induced by the canonical NF-κB pathway, and subsequently boosted and continued via non-canonical NF-κB signaling through stabilization of NIK. NF-κB subunits p65 and p52 can both bind to the Bcl-XL promoter and activate transcription upon CD40 stimulation. Moreover, canonical NF-κB signaling was correlated with Bfl-1 expression, whereas Mcl-1 in contrast, was not transcriptionally regulated by NF-κB. Finally, we applied a novel compound targeting NIK to selectively inhibit the non-canonical NF-κB pathway and showed that venetoclax-resistant CLL cells were sensitized to venetoclax. In conclusion, protective signals from the CLL microenvironment can be tipped towards apoptosis sensitivity by interfering with non-canonical NF-κB signaling.

ORCID iDs

Haselager, Marco, Thijssen, Rachel, West, Christopher ORCID logoORCID: https://orcid.org/0000-0002-0115-2060, Young, Louise, Van Kampen, Roel, Willmore, Elaine, Mackay, Simon ORCID logoORCID: https://orcid.org/0000-0001-8000-6557, Kater, Arnon and Eldering, Eric;
CORE (COnnecting REpositories)