Combined Patterns of IGHV Repertoire and Cytogenetic/Molecular Alterations in Monoclonal B Lymphocytosis versus Chronic Lymphocytic Leukemia

Abstract

BackgroundChronic lymphocytic leukemia (CLL)-like monoclonal B lymphocytosis (MBL) with (MBLhi) or without (MBLlo) absolute B-lymphocytosis precedes most CLL cases,the specific determinants for malignant progression remaining unknown.Methodology/Principal FindingsFor this purpose, simultaneous iFISH and molecular analysis of well-established cytogenetic alterations of chromosomes 11, 12, 13, 14 and 17 together with the pattern of rearrangement of the IGHV genes were performed in CLL-like cells from MBL and CLL cases. Our results based on 78 CLL-like MBL and 117 CLL clones from 166 subjects living in the same geographical area, show the existence of three major groups of clones with distinct but partially overlapping patterns of IGHV gene usage, IGHV mutational status and cytogenetic alterations. These included a group enriched in MBLlo clones expressing specific IGHV subgroups (e.g. VH3-23) with no or isolated good-prognosis cytogenetic alterations, a second group which mainly consisted of clinical MBLhi and advanced stage CLL with a skewed but different CLL-associated IGHV gene repertoire (e.g. VH1-69), frequently associated with complex karyotypes and poor-prognosis cytogenetic alterations, and a third group of clones with intermediate features, with prevalence of mutated IGHV genes, and higher numbers of del(13q)+ clonal B-cells.Conclusions/SignificanceThese findings suggest that the specific IGHV repertoire and IGHV mutational status of CLL-like B-cell clones may modulate the type of cytogenetic alterations acquired, their rate of acquisition and/or potentially also their clinical consequences. Further long-term follow-up studies investigating the IGHV gene repertoire of MBLlo clones in distinct geographic areas and microenvironments are required to confirm our findings and shed light on the potential role of some antigen-binding BCR specificities contributing to clonal evolution.

Subjects with chronic lymphocytic leukaemia‐like B‐cell clones with stereotyped B‐cell receptors frequently show MDS‐associated phenotypes on myeloid cells

“…Biassed usage of specific IGHV genes in both CLL and MBL (Henriques et al, 2013;Vardi et al, 2013) would further support the existence of selective pressurese.g. inherited genetic predisposition factors and/or still unidentified pathogen(s) -that may favour the expansion of specific IGHV-IGHD-IGHJ clones, not only at the B-lymphocyte stage but potentially also at the haematopoeitic stem cell (HSC) compartment (Alizadeh & Majeti, 2011).…”

“…Diagnosis of MBL and CLL was based on the World Health Organization (WHO) 2008 criteria (Swerdlow et al, 2008) and clinical staging of CLL subjects was established according to the Binet classification (Binet et al, 1981). Immunophenotypic evaluation of the B-cell clones in MBL cases and both CLL and other B-CLPD patients was performed as previously described (Nieto et al, 2010;Henriques et al, 2013Henriques et al, , 2014. Overall, 37/200 subjects (18%) showed co-existence of two or three phenotypically different aberrant B-cell populations with a CLL-like (n = 33) or other B-CLPD phenotype (n = 4).…”

“…Cytogenetic analyses were performed by multicolour interphase fluorescence in situ hybridization on slides containing fluorescence-activated cell sorting (FACS)-purified and fixed aberrant B-cells, as previously described in detail (Quijano et al, 2008;Henriques et al, 2013Henriques et al, , 2014. In parallel, analysis of the rearrangement patterns of the immunoglobulin heavy chain variable region genes (IGHV) was performed for each FACS-purified B-cell clone (van Dongen et al, 2003;Gonz alez et al, 2003;Henriques et al, 2013Henriques et al, , 2014.…”

“…In parallel, analysis of the rearrangement patterns of the immunoglobulin heavy chain variable region genes (IGHV) was performed for each FACS-purified B-cell clone (van Dongen et al, 2003;Gonz alez et al, 2003;Henriques et al, 2013Henriques et al, , 2014. Forward and reverse sequences were aligned into a single resolved sequence and then aligned with germline sequences using the ImMunoGeneTics (IMGT) database and tools (http://www.imgt.org/ IMGT_vquest/share/textes/).…”

A plant-made cholera toxin B subunit enhances mucosal wound healing and protects against ulcerative colitis and colon cancer.

“…There is a paucity of experimental data examining long-term effects of leukocytosis. In monoclonal B lymphocytosis, a subcategory of leukocytosis, the clinical course is asymptomatic with a very small number of cases progressing to chronic lymphocytic leukemia (CLL) (212). More work should be done to determine if there is an enhanced risk of developing leukemia from long-term CTBp administration but most cases of leukocytosis are found to be benign.…”