CD6 expression is an independent predictor of time to first treatment in chronic lymphocytic leukemia

CD6 is a lymphocytic receptor expressed by all T cells and a subset of B and natural killer (NK) cells. It physically associates with the antigen-specific clonotypic receptor of T (TCR) cells, where it modulates the activation and differentiation signals delivered along lymphocyte development and upon peripheral antigen recognition. CD6 is also expressed in some B-cell malignancies (e.g., chronic lymphocytic leukemia [CLL]), though its biological role and clinical performance is largely unknown. To this end, we have evaluated the potential impact of CD6 differential expression in a CLL patient cohort. 270 CLL patient case histories from the CLL-ES project with available RNA-Seq data have been analyzed. High CD6 expression was found to be associated with mutated IGHV status and predictive of longer time to first treatment in a uni- and multi-variable model. Ten-year probability of receiving treatment was 33% vs. 55% in the CD6hi and CD6lo groups, respectively (P=0.0003), along with the lymphocyte count and the CLL International Prognostic Index. Further Gene Set Enrichment Analyses showed association of high CD6 expression with downregulation of MYC-regulated, mitotic spindle-related, and RNA splicing-associated genes, all positively related to cancer progression. Interestingly, CD38, a widely studied adverse prognostic marker in CLL, was significantly down-regulated in the CD6hi group, in agreement with flow cytometry data. These results reinforce the notion that CD6 may play a pivotal role in neoplastic B-cell biology and lay the ground to further explore CD6 expression in the context of CLL prognoses.