In conclusion, we demonstrated that JAK–STAT signalling may shape the NF‐κB response in CLL towards venetoclax sensitivity or resistance via Bcl‐XL, involving multiple regulatory crosstalk mechanisms, thereby providing multiple potential targets for the downregulation of Bcl‐XL, which could be applied in combination therapy for CLL. Here, NFKB1 is linked to B-cell chronic lymphocytic leukemia.