High CXCR3 on Leukemic Cells Distinguishes IgHV(mut) from IgHV(unmut) in Chronic Lymphocytic Leukemia: Evidence from CD5(high) and CD5(low) Clones

Despite the shared pattern of surface antigens, neoplastic cells in chronic lymphocytic leukemia (CLL) are highly heterogeneous in CD5 expression, a marker linked to a proliferative pool of neoplastic cells. To further characterize CD5(high) and CD5(low) neoplastic cells, we assessed the chemokine receptors (CCR5, CCR7, CCR10, CXCR3, CXCR4, CXCR5) and adhesion molecules (CD54, CD62L, CD49d) on the CD5(high) and CD5(low) subpopulations, defined by CD5/CD19 coexpression, in peripheral blood of CLL patients (n = 60) subgrouped according to the IgHV mutational status (IgHV(mut), n = 24; IgHV(unmut), n = 36). CD5(high) subpopulation showed a high percentage of CXCR3 (P < 0.001), CCR10 (P = 0.001), and CD62L (P = 0.031) and high levels of CXCR5 (P = 0.005), CCR7 (P = 0.013) compared to CD5(low) cells expressing high CXCR4 (P < 0.001). Comparing IgHV(mut) and IgHV(unmut) patients, high levels of CXCR3 on CD5(high) and CD5(low) subpopulations were detected in the IgHV(mut) patients, with better discrimination in CD5(low) subpopulation. Levels of CXCR3 on CD5(low) subpopulation were associated with time to the next treatment, thus further confirming its prognostic value. Taken together, our analysis revealed higher CXCR3 expression on both CD5(high) and CD5(low) neoplastic cells in IgHV(mut) with a better prognosis compared to IgHV(unmut) patients. Contribution of CXCR3 to CLL pathophysiology and its suitability for prognostication and therapeutic exploitation deserves future investigations.