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.
Highlights
Monoclonal B lymphocytosis (MBL) is defined by the presence of a low to moderate expansion of circulating clonal B lymphocytes (,56109/L) –most frequently resembling the phenotype of chronic lymphocytic leukemia (CLL) cells (CLL-like cells)– in otherwise healthy adults, in the absence of symptoms and signs of an underlying chronic lymphoid malignancy [1,2]
NOTCH1 mutations occurred in 5/52 Chronic lymphocytic leukemia (CLL) cases (10%), in which a preferential association with immunoglobulin heavy chain variable region (IGHV) unmutated clones (80%, P = 0.02) and a high frequency of cases (3/5, 60%) harbouring trisomy 12 as an additional isolated chromosomal abnormality (P = 0.007) was observed; in the remaining two CLL cases, the presence of NOTCH1 mutation was associated with del(13q14) involving the RB1 gene and to both del(13q14.3) and del(17p), respectively
Significant differences were found between aMBLhi vs CLL, bMBLlo vs CLL, cMBLlo vs monoclonal B lymphocytosis (MBL) with (MBLhi), d MBLlo plus MBLhi vs CLL and eMBLlo vs MBLhi plus CLL; NS, no statistically significant differences observed (P$0.05);BCR, B-cell receptor; CLL, chronic lymphocytic leukemia; monoclonal B lymphocytosis (MBL), monoclonal B-cell lymphocytosis; aa, aminoacids; HCDR3,heavy chain complementarity-determining region 3
Summary
Monoclonal B lymphocytosis (MBL) is defined by the presence of a low to moderate expansion of circulating clonal B lymphocytes (,56109/L) –most frequently resembling the phenotype of chronic lymphocytic leukemia (CLL) cells (CLL-like cells)– in otherwise healthy adults, in the absence of symptoms and signs of an underlying chronic lymphoid malignancy [1,2]. Recent multiparameter flow cytometry studies have demonstrated that CLL-like MBL clones can be found in a significant proportion of healthy adults over 40 years. Their frequency ranges from 3.5% to around 12% of the general population, and between 13% to 18% of first-degree relatives of CLL patients, depending on the sensitivity of the technique [3]. Chronic 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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
