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

(CLL) B cells, but not on normal postpartum tissues. ROR1 is a receptor for Wnt5a that maycomplexwithTCL1,acoactivatorofAKTthatisabletopromotedevelopmentofCLL. 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 distinguishedfromthosethatwereROR1 Pos inunsupervisedgene-expressionclustering 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 thresholdforROR1surfaceexpressionthatcouldsegregatesamplesofthetrainingsetintoROR1-HivsROR1-Losubgroupsthatdiffered significantlyintheir median treatment-free survival (TFS).Using this threshold, we foundthatROR1-Hi cases hadasignificantlyshorter medianTFSandoverallsurvivalthanROR1-Locasesinthevalidationset.ThesedatademonstratethatexpressionofROR1maypromote leukemia-cell activation and survival and enhance disease progression in patients with CLL. ( Blood . 2016;128(25):2931-2940)