Although BH3-mimetic venetoclax was extremely cytotoxic for chronic lymphocytic leukemia (CLL) cells, some patients with CLL fail to clear minimal residual disease (MRD). The researchers evaluated the CLL cells of 7 individuals with CLL who had been treated previously (CLL1-7) and discovered that each had ROR1 high expression. The researchers discovered that the levels of ROR1 expressed on CLL cells at SC2 were significantly higher than those on CLL cells collected at SC1 by comparing the expression levels of this molecule in CLL samples from such patients before and after therapy with SC1 (Sample Collection 2 (SC2)) when they had progressive increases in MRD. The researchers observed upregulation of genes induced by Wnt5a-induced ROR1 signalling in SC2 as well. BCL2L1, for example, was upregulated. Transduction of the CLL-cell-line MEC1 to express ROR1 increased expression of target genes induced by ROR1 signaling, BCL-XL expression, and resistance to venetoclax, even in cells made to express mutant forms of BCL2 that are associated with resistance to venetoclax. Treatment of CLL cells with Wnt5a increased resistance to venetoclax, an effect that was blocked by the ROR1 mAb (UC-961, zilovertamab).According to the research, Wnt5a-induced ROR1 signaling may have enhanced response to venetoclax treatment.