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 CD5high and CD5low neoplastic cells, we assessed the chemokine receptors (CCR5, CCR7, CCR10, CXCR3, CXCR4, CXCR5) and adhesion molecules (CD54, CD62L, CD49d) on the CD5high and CD5low subpopulations, defined by CD5/CD19 coexpression, in peripheral blood of CLL patients (n = 60) subgrouped according to the IgHV mutational status (IgHVmut, n = 24; IgHVunmut, n = 36). CD5high 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 CD5low cells expressing high CXCR4 (P < 0.001). Comparing IgHVmut and IgHVunmut patients, high levels of CXCR3 on CD5high and CD5low subpopulations were detected in the IgHVmut patients, with better discrimination in CD5low subpopulation. Levels of CXCR3 on CD5low 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 CD5high and CD5low neoplastic cells in IgHVmut with a better prognosis compared to IgHVunmut patients. Contribution of CXCR3 to CLL pathophysiology and its suitability for prognostication and therapeutic exploitation deserves future investigations.
Highlights
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative malignancy of clonally expanded heterogeneous pool of neoplastic B cells with aberrant expression of CD5 [1, 2], which are highly variably distributed between bone marrow, lymphoid organs, and peripheral blood
There is a growing body of evidence that proliferation of neoplastic cells plays a critical role in CLL pathogenesis [3,4,5], with the highest degree of proliferation being observed in the lymph nodes [6]
The overlapping B-cell receptor (BCR) repertoires between CD5high and CD5low cells suggest a dynamic relationship of these two B-CLL cell Journal of Immunology Research subpopulations [2]
Summary
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative malignancy of clonally expanded heterogeneous pool of neoplastic B cells with aberrant expression of CD5 [1, 2], which are highly variably distributed between bone marrow, lymphoid organs, and peripheral blood. There is a growing body of evidence that proliferation of neoplastic cells plays a critical role in CLL pathogenesis [3,4,5], with the highest degree of proliferation being observed in the lymph nodes [6]. CD5, a marker normally present on T cells, acts as a repressor of B-cell receptor (BCR) signalling in CLL [7]. The overlapping BCR repertoires between CD5high and CD5low cells suggest a dynamic relationship of these two B-CLL cell. It has been shown that CXCR4dimCD5bright “proliferative” cells overexpress more “cell division” genes, while CXCR4brightCD5dim “resting” cells express higher levels of “antiproliferative” genes, suggesting that the last subset could be a distinct self-renewing one from which all clonal members derive [8, 9]
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