The chronic lymphocytic leukemia (CLL) immunoglobulin repertoire is biased and characterized by the existence of subsets of cases with closely homologous ("stereotyped") complementarity-determining region 3 (CDR3) sequences. In the present series, 201 (21.9%) of 916 patients with CLL expressed IGHV genes that belonged to 1 of 48 different subsets of sequences with stereotyped heavy chain (H) CDR3. Twenty-six subsets comprised 3 or more sequences and were considered "confirmed." The remaining subsets comprised pairs of sequences and were considered "potential"; public database CLL sequences were found to be members of 9 of 22 "potential" subsets, thereby allowing us to consider them also "confirmed.

Chronic lymphocytic leukemia (CLL) immunoglobulin repertoire is biased. Furthermore, subsets of closely homologous (“stereotyped”) complementarity-determining region 3 (CDR3) sequences were recently described in CLL patients. In the present study, we evaluated the frequency and characteristics of these homologous subsets in a cohort of 916 CLL patients. We report that 201 cases (21.9%) expressed IGHV genes which belonged to one of 48 different subsets of sequences with stereotyped heavy chain (H) CDR3, of which only ten have been reported previously. Within each stereotyped HCDR3 subset, the IG sequences might show the usage of identical or different IGHV genes. In the latter case, the IGHV genes most often belonged to the same IGHV subgroup or clan or carried homologous HCDR1. Each subset included up to 20 cases. A similar proportion of HCDR3 restriction (80/462 cases; 17.3%) was found among public-database CLL sequences; comparison to 6430 non-CLL public database IGHV-D-J sequences showed that this is a “CLL-related” feature. In our series, the chance of belonging to a subset was even (p<0.001) higher for unmutated IGHV sequences (35%); furthermore, it exceeded 30% in cases using selected IGHV genes (e.g., IGHV3-21/1-69/1-2/1-3/4-39/3-48). Database and literature searches revealed that 64/916 CLL cases belonging to seven different subsets displayed HCDR3 homology with various autoantibodies, including rheumatoid factors and anti-cardiolipin antibodies. In our series, CLL cases with selected stereotyped IGs were also found to share unique biological and clinical features. In particular, cases expressing stereotyped IGHV4-34/IGKV2-30 B cell receptors (BCRs) were of significantly younger age and followed a strikingly indolent disease, whereas those expressing, IGHV3-21/IGLV3-21 BCRs experienced an aggressive disease, regardless of IGHV mutation status. Furthermore, among patients expressing unmutated IGHV1-69 genes, we identified a subset (IGHV1-69/IGHD3-10/IGHJ6) with higher overall survival (OS) compared to another subset (IGHV1-69/IGHD2-2/IGHJ6) with significantly shorter OS (log Rank test=0.05). In conclusion, the unique, “CLL-biased” molecular features of stereotyped HCDR3 sequences suggest a role for antigen not only in driving the cell of origin but also in determining the clinical features and outcome for at least some CLL patients. Considering the clinical-biological associations with certain subsets, it is conceivable that future therapeutic decisions should be based not only on mutational status of IGHV genes but also on individual HCDR3 characteristics.

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The responsiveness and diversity of peripheral B-cell repertoire decreases with age, possibly because of B-cell clonal expansions, as suggested by the incidence of serum monoclonal immunoglobulins and of monoclonal chronic lymphocytic leukemia (CLL)-like B lymphocytes in clinically silent adults. We phenotyped peripheral blood cells from 500 healthy subjects older than 65 years with no history or suspicion of malignancies and no evidence of lymphocytosis. In 19 cases (3.8%) a / ratio of more than 3:1 or less than 1:3 was found: 9 were CD5 ؉ , CD19 ؉ , CD23 ؉ , CD20 low , CD79b low , sIg low (classic CLL-like phenotype); 3 were CD5 ؉ , CD19 ؉ , CD23 ؉ , CD20 high , CD79b low , sIg low (atypical CLL-like), and 7 were CD5 ؊ , CD19 ؉ , CD20 high , CD23 ؊ , CD79b bright , FMC7 ؉ , sIg bright (non-CLL-like). In 2 subjects, 2 phenotypically distinct unrelated clones were concomitantly evident. No cases were CD10 ؉ . Polymerase chain reaction ( IntroductionIt is now well established that with aging both humans and mice tend to produce an antibody response of limited heterogeneity with respect to isotype, antigen-binding affinity, idiotype, and heavy chain variable (V H ) gene use. 1 The cause for these phenomena is so far unknown. They are not due to a primary defect of B-cell precursors nor to abnormalities of bone marrow (BM) environment, as indicated by BM transplantation experiments in mice. 2 They may reflect, at least in part, the decreased number of B-cell precursors that are observed within the BM of aging humans and mice, 3-5 though B-cell generation continues unabated during adulthood, and can also be ascribed to altered helper T-cell activity. 6,7 One intriguing possibility is that the age-related limited diversity of the B-cell repertoire may be accounted for by the appearance of B-cell clonal expansions. The most striking example is provided by the age-associated increasing incidence of serum monoclonal immunoglobulins, which occurs in both mice and humans (monoclonal gammopathies of undetermined significance [MGUS]). 8,9 In addition, the observation that expanded clones of Ly-1 ϩ B cells are universally detectable in senescent normal mice 1,10,11 is mirrored by the recent finding that monoclonal CD5 ϩ B lymphocytes are present in a relevant number of clinically silent adults. 12 The phenotype of circulating monoclonal cells (CD5 ϩ , CD19 ϩ , CD23 ϩ , CD20 low , CD79b low , sIg low ) resembles very closely that of chronic lymphocytic leukemia (CLL). These clones have been detected with increased frequency among relatives of patients with CLL. 13 In this context it is of interest that first degree relatives of patients with CLL have a risk of developing CLL, as well as other lymphoid malignancies, which is more than 3 times greater than the risk of the general population. 14 To approach the problem of the relationship between agerelated progressive restriction of the B-cell repertoire and the development of B-cell malignancies, we aimed at defining whether clonal expansions of B-lymphocyte subsets different...

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