High-level ROR1 associates with accelerated disease-progression in chronic lymphocytic leukemia
Menée sur 1 568 patients atteints d'une leucémie lymphocytaire chronique, cette étude met en évidence une association entre un niveau élevé d'expression du récepteur ROR1 sur les cellules cancéreuses et une progression plus rapide de la maladie
ROR1 is an oncoembryonic orphan-receptor found on chronic lymphocytic leukemia (CLL) B cells, but not on normal post-partum tissues. ROR1 is a receptor for Wnt5a that may complex with TCL1, a co-activator of AKT that is able to promote development of CLL. We found the CLL cells of a few patients expressed negligible ROR1 (ROR1Neg), but expressed TCL1A at levels comparable to those of samples that expressed ROR1 (ROR1Pos). Transcriptome analyses revealed that ROR1Neg cases generally could be distinguished from those that were ROR1Pos in unsupervised gene-expression clustering analysis. Gene-set enrichment analyses demonstrated that ROR1Neg CLL had lower expression and activation of AKT-signaling pathways relative to ROR1Pos CLL, similar to what was noted for leukemia that respectively developed in TCL1 versus ROR1xTCL1 transgenic mice. In contrast to its effect on ROR1Pos CLL, Wnt5a did not enhance the proliferation, chemotaxis, or survival of ROR1Neg CLL. We examined the CLL cells from 1,568 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 versus 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.
Blood , résumé, 2015