BIRC3 expression predicts CLL progression and defines treatment sensitivity via enhanced NF-{kappa}B nuclear translocation

Purpose: Chronic lymphocytic leukemia (CLL) pathophysiology is characterized by a complex crosstalk of tumor cells with the microenvironment. In this regard, NF-kB signaling is considered as important signaling axis, with a variety of key molecules aberrantly expressed or genetically altered in CLL patients. One of these molecules is BIRC3 (cIAP2), a central regulator of non-canonical NF-kB signaling that serves as pathway brake in the absence of microenvironmental signals. However, the contribution of BIRC3 expression to CLL progression and potential therapeutic implications is unknown. Experimental Design: We analyzed the role of BIRC3 mRNA expression in primary CLL samples in correlation to clinical datasets and used ex vivo assays to investigate functional consequences on the level of NK-kB signaling and downstream target gene regulation. For proof of principle experiments, we used genetically modified cell lines. Results: We demonstrate that CLL patients with low BIRC3 expression experience a more rapid disease progression, which coincides with an enhanced activation of canonical NF-kB target genes evidenced by an increased p65/Rel-B nuclear translocation ratio. As a consequence of enhanced canonical NF-kB target gene activation, both anti- and proapoptotic Bcl-2 family members were upregulated in BIRC3^low primary CLL cells, which was associated with higher sensitivity to Venetoclax treatment in vitro. Conclusion: Here we show the impact of BIRC3 expression in CLL disease progression in the absence of BIRC3 mutations and show altered canonical NF-kB target gene activation with therapeutic implications.

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