Abstract
BackgroundB cell receptor Immunoglobulin (BcR IG) repertoire of Chronic Lymphocytic Leukemia (CLL) is characterized by the expression of quasi-identical BcR IG. These are observed in approximately 30% of patients, defined as stereotyped receptors and subdivided into subsets based on specific VH CDR3 aa motifs and phylogenetically related IGHV genes. Although relevant to CLL ontogeny, the distribution of CLL-biased stereotyped immunoglobulin rearrangements (CBS-IG) in normal B cells has not been so far specifically addressed using modern sequencing technologies. Here, we have investigated the presence of CBS-IG in splenic B cell subpopulations (s-BCS) and in CD5+ and CD5− B cells from the spleen and peripheral blood (PB).MethodsFractionation of splenic B cells into 9 different B cell subsets and that of spleen and PB into CD5+ and CD5− cells were carried out by FACS sorting. cDNA sequences of BcR IG gene rearrangements were obtained by NGS. Identification of amino acidic motifs typical of CLL stereotyped subsets was carried out on IGHV1-carrying gene sequences and statistical evaluation has been subsequently performed to assess stereotypes distribution.ResultsCBS-IG represented the 0.26% average of IGHV1 genes expressing sequences, were detected in all of the BCS investigated. CBS-IG were more abundant in splenic and circulating CD5+ B (0.57%) cells compared to CD5− B cells (0.17%). In all instances, most CBS IG did not exhibit somatic hypermutation similar to CLL stereotyped receptors. However, compared to CLL, they exhibited a different CLL subset distribution and a broader utilization of the genes of the IGHV1 family.ConclusionsCBS-IG receptors appear to represent a part of the “public” BcR repertoire in normal B cells. This repertoire is observed in all BCS excluding the hypothesis that CLL stereotyped BcR accumulate in a specific B cell subset, potentially capable of originating a leukemic clone. The different relative representation of CBS-IG in normal B cell subgroups suggests the requirement for additional selective processes before a full transformation into CLL is achieved.
Highlights
Chronic lymphocytic leukemia (CLL) is characterized by pronounced clinical heterogeneity that likely reflects the underlying biological complexity (Chiorazzi and Ferrarini 2011; Zenz et al 2010)
Processing of sequence data and identification of CLLbiased stereotyped immunoglobulin gene rearrangements (CBS-IG) of the splenic B cell subpopulations (s-BCS) A total of 182,783 productive, unique IGHV1 subgroup gene rearrangement curated sequences were obtained from 1,315,000 sorted B cells (~ 18%) from six spleens separated as detailed in Supplementary Fig. 1
Two hundred and seventy-nine immunoglobulin heavy variable (IGHV)-IGHD-IGHJ gene rearrangements were assigned to one of the major IGHV1 Chronic Lymphocytic Leukemia (CLL) stereotyped subsets corresponding to 0.24% of all identified clonal families
Summary
Chronic lymphocytic leukemia (CLL) is characterized by pronounced clinical heterogeneity that likely reflects the underlying biological complexity (Chiorazzi and Ferrarini 2011; Zenz et al 2010). A fundamental aspect of CLL ontogeny and evolution concerns microenvironmental interactions mediated through various surface receptors, amongst which the B cell receptor immunoglobulin (BcR IG) plays perhaps the most prominent role This is amply demonstrated by the segregation of CLL cases into two subgroups with widely divergent clinical courses based on the impact of the somatic hypermutation (SHM) burden within the clonotypic rearranged immunoglobulin heavy variable (IGHV) gene. B cell receptor Immunoglobulin (BcR IG) repertoire of Chronic Lymphocytic Leukemia (CLL) is characterized by the expression of quasi-identical BcR IG These are observed in approximately 30% of patients, defined as stereotyped receptors and subdivided into subsets based on specific VH CDR3 aa motifs and phylogenetically related IGHV genes. Identification of amino acidic motifs typical of CLL stereotyped subsets was carried out on IGHV1-carrying gene sequences and statistical evaluation has been subsequently performed to assess stereotypes distribution
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