Pathogenetic Implications from the Analysis of Immunoglobulin Genes in Chronic Lymphocytic Leukemia of Mediterranean Ancestry: The Lesson of the IGHV3-21 Gene.

Studies of the characteristics and the mutational status of the immunoglobulin (Ig) genes expressed by Chronic Lymphocytic Leukemia (CLL) suggest a potential role for antigenic stimulation in the pathogenesis and/or evolution of the disease. We analyzed IGHV repertoire and mutational status in 553 CLL patients from the Mediterranean area. The most commonly represented IGHV genes mirror the usage of normal B cells, with the exception of IGHV1-18, IGHV3-30.3 and IGHV4-59 that are underrepresented. In addition, the analysis of the IGHV3-21 gene, frequently present in Northern European CLL, showed the following peculiarities: 1) this gene was expressed only in a limited number of cases in our Mediterranean cohort (16/553; 2.9%); 2) based on HCDR3 cluster analysis, IGHV3-21-utilizing cases could be grouped in two different subsets of similar frequency. The first subset (common-HCDR3 subset) included seven cases (out of 16), which carried a very short and virtually identical HCDR3 aminoacid sequence bearing strong similarities to the Northern European IGHV3-21 CLL (Tobin et al, Blood. 2002 Mar 15;99(6):2262–4). All cases used the IGHJ6 gene; 4/7 were unmutated; 6/7 carried the V_λ2-14 (IGLV3-21) light chain gene with a similar LCDR3; all expressed CD38 and had a progressive disease. The second subset (non-homogeneous-HCDR3 subset) included 9 cases and was characterized by long and heterogeneous HCDR3 rearrangements, with diverse IGHJ and IGV light chain gene usage and variable CD38 expression; five out of 9 cases were unmutated; the clinical course of these patients was variable (only 4/9 progressed). The first subset, with the evidence of a similar CDR3 in so many different CLL cohorts, suggests the existence of a specific, yet undefined, antigenic element that may subsequently lead to a more aggressive clinical course. The dramatically different frequency of this subset as compared to Northern Europe suggests that the potential selecting agent may be less frequently encountered in the Mediterranean area. In contrast, the second subset included cases with heterogeneous HCDR3 rearrangements and a variable clinical outcome. This second subset may mirror the heterogeneity and low frequency of expression of IGHV3-21 rearrangements in the normal repertoire of peripheral blood B cells, as shaped by the germline composition, molecular mechanisms and distinct selective influences.