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

Abstract

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 transgenic mice. 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 ROR1 surface expression that could segregate samples of the training set into ROR1-Hi vs ROR1-Lo subgroups that differed significantly in their median treatment-free survival (TFS). Using this threshold, we found that ROR1-Hi cases had a significantly shorter median TFS and overall survival than ROR1-Lo cases in the validation set. These data demonstrate that expression of ROR1 may promote leukemia-cell activation and survival and enhance disease progression in patients with CLL.