JAK-STAT signalling shapes the NF-κB response in CLL towards venetoclax sensitivity or resistance via Bcl-XL

Preventing or overcoming resistance to the Bcl-2 inhibitor venetoclax is an emerging unmet clinical need in patients with chronic lymphocytic leukaemia (CLL). The upregulation of anti-apoptotic Bcl-2 members through signalling pathways within the tumor microenvironment appears as a major factor leading to resistance to venetoclax. Previously, we reported that T cells can drive resistance through CD40 and non-canonical NF-kappa B activation and subsequent Bcl-XL induction. Moreover, the T cell-derived cytokines IL-21 and IL-4 differentially affect Bcl-XL expression and sensitivity to venetoclax via unknown mechanisms. Here, we mechanistically dissected how Bcl-XL is regulated in the context of JAK-STAT signalling in primary CLL. First, we demonstrated a clear antagonistic role of IL-21/STAT3 signalling in the NF-kappa B-mediated expression of Bcl-XL, whereas IL-4/STAT6 further promoted the expression of Bcl-XL. In comparison, Bfl-1, another NF-kappa B target, was not differentially affected by either cytokine. Second, STAT3 and STAT6 affected Bcl-XL transcription by binding to its promoter without disrupting the DNA-binding activity of NF-kappa B. Third, in situ proximity ligation assays (isPLAs) indicated crosstalk between JAK-STAT signalling and NF-kappa B, in which STAT3 inhibited canonical NF-kappa B by accelerating nuclear export, and STAT6 promoted non-canonical NF-kappa B. Finally, NF-kappa B inducing kinase (NIK) inhibition interrupted the NF-kappa B/STAT crosstalk and resensitized CLL cells to venetoclax. In conclusion, we uncovered distinct crosstalk mechanisms that shape the NF-kappa B response in CLL towards venetoclax sensitivity or resistance via Bcl-XL, thereby revealing new potential therapeutic targets.

Automated summary

Resistance to venetoclax, a Bcl-2 inhibitor, is a significant problem in CLL patients. The upregulation of Bcl-2 through signaling pathways in the tumor microenvironment contributes to this resistance. T cells can drive resistance through CD40 and non-canonical NF-kappa B activation. The cytokines IL-21 and IL-4 from T cells differentially affect Bcl-XL expression and sensitivity to venetoclax. Mechanistic studies revealed the role of JAK-STAT signaling and NF-kappa B in regulating Bcl-XL expression, providing potential therapeutic targets for overcoming venetoclax resistance.