High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia

ROR1 is an oncoembryonic orphan receptor found on chronic lymphocytic leukemia (CLL) B cells, but not on normal postpartum tissues. ROR1 is a receptor for Wnt5a that may complex with TCL1, a coactivator of AKT that is able to promote development of CLL. We found the CLL cells of a few patients expressed negligible ROR1 (ROR1(Neg)), but expressed TCL1A at levels comparable to those of samples that expressed ROR1 (ROR1 Pos). Transcriptome analyses revealed that ROR1(Neg) cases generally could be distinguished from those that were ROR1 Pos in unsupervised gene-expression clustering analysis. Gene-set enrichment analyses demonstrated that ROR1(Neg) CLL had lower expression and activation of AKT signaling pathways relative to ROR1 Pos CLL, similar to what was noted for leukemia that respectively developed in TCL1 vs ROR1xTCL1 transgenicmice. In contrast to its effect on ROR1 Pos CLL, Wnt5a did not enhance the proliferation, chemotaxis, or survival of ROR1(Neg) CLL. We examined the CLL cells from 1568 patients, which we randomly assigned to a training or validation set of 797 or 771 cases, respectively. Using recursive partitioning, we defined a threshold for ROR1surfaceexpressionthatcouldsegregatesamplesof thetrainingset intoROR1-Hi vsROR1-Losubgroupsthatdiffered significantly in theirmedian treatment-free survival (TFS). Using this threshold, we found thatROR1-Hi cases had a significantly shorter medianTFSandoverallsurvival thanROR1-Locasesin the validationset. Thesedatademonstrate that expressionofROR1maypromote leukemia-cell activation and survival and enhance disease progression in patients with CLL.