High CXCR3 on Leukemic Cells Distinguishes IgHV mut from IgHV unmut in Chronic Lymphocytic Leukemia: Evidence from CD5high and CD5low Clones

Abstract

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.