Molecular and clinical features of chronic lymphocytic leukaemia with stereotyped B cell receptors: results from an Italian multicentre study

Abstract

A fraction of chronic lymphocytic leukaemia (CLL) cases carry highly homologous B-cell receptors (BCR), i.e. characterized by non-random combinations of immunoglobulin heavy-chain variable (IGHV) genes and heavy-chain complementarity determining region-3 (HCDR3), often associated with a restricted selection of IGVK/L light chains. Such 'stereotyped' BCR occur more frequently in CLL with unmutated (UM) than mutated (M) IGHV genes. We analysed 1426 IG rearrangements (from 1398 CLL cases) by a clustering driven by HCDR3 similarities. Molecular findings were correlated to time-to-treatment (TTT) and presence of known prognosticators. Sixty-nine clusters (319 IG-rearrangements, 22AE4%) with stereotyped BCR were identified. Among 30 confirmed clusters ( ‡3 IG-rearrangements/cluster), we found 14 novel clusters, of which 11 had M IG rearrangements (M clusters) and predominantly (8/11) used IGHV3 subgroup genes. Recurrent cluster-biased amino acid changes were found throughout IGHV sequences of these 'M clusters'. Regarding clinical outcome: (i) UM CLL from the IGHV1-2/1-3/1-18/1-46/7-4-1/IGKV1-39 cluster had poorer prognosis than UM/M cases, or UM cases using the same IGHV genes but not in clusters; (ii) M CLL from the IGHV3-21/IGLV3-21 cluster had TTT similar to UM CLL, and shorter than M CLL expressing IGHV3-21 but not in cluster. Altogether, our analysis identified additional molecular and clinical features for CLL expressing stereotyped BCR.

Immunoglobulin sequence analysis and prognostication in CLL: guidelines from the ERIC review board for reliable interpretation of problematic cases

“…A possible exception could be cases carrying a rearrangement of the IGHV3-21 gene. As in most studies this gene has been correlated with a poor clinical outcome, [18][19][20][21][22][23] cases with double rearrangements of which one is mutated productive and employs the IGHV3-21 gene could be considered as having unfavorable prognosis, in particular when showing a stereotyped VH CDR3.…”

Next generation RNA‐sequencing in prognostic subsets of chronic lymphocytic leukemia

“…However, patients with extreme obesity (i.e., BMI >40 kg/m 2 ), a major risk factor for VTE [1,5,6], were under-represented in VTE prophylaxis trials of enoxaparin (40 mg once daily (QDay)) in medically ill patients [3,7]. Obesity affects drug distribution and kinetics [1,2,8].…”

“…Moreover, CLL is characterized by multiple subsets carrying quasi-identical or ''stereotyped'' B-cell receptors which imply a role for antigen selection in leukemogenesis [3]. Recently, certain subsets have also been shown to share clinico-biological features [3,4]; for instance, subset #1 patients, which uniformly express unmutated IGHV1/5/7 together with IGKV1(D)-39 genes and a stereotyped heavy complementarity determining region 3 (VH CDR3) of 13-14 amino acids, have a significantly inferior outcome compared to patients expressing the same IGHV genes but without stereotypy [3,5]. In contrast, subset #4 patients (IGHV4-34/IGKV2-30 usage and VH CDR3 of 20 amino acids), have a low median age at diagnosis, express surface IgG and have an indolent disease [3].…”

1086 IGHV1-69 as a Promising Candidate for the Development of a Shared Immunotherapy to B-cell Lymphomas

“…These analysis, carried out on very broad cohorts of patients, revealed an over-representation of certain IGHV genes among clustered cases, especially V H 3-21 and V H 1-69, and an under-presentation of others, as for example V H 3-7, V H 3-23, V H 3-30 [27][28][29]. Interestingly, Darzentas et al observed that just six IGHV genes (V H 1-69, V H 1-3, V H 1-2, V H 3-21, V H 4-34 and V H 4-39) accounted for almost 80% of cases belonging to high-level clusters with stereotyped BCR structures [29].…”

“…Moreover, studies in different lymphoma types (B-CLL, follicular lymphoma, MALT lymphomas) indicated that lymphoma cells are able to recognize autoantigens or foreign antigens, and that stimulation by antigen binding contributes to survival and proliferation of lymphoma cells [18]. Recently, the characterization of several subgroups of B-CLL revealed the expression of strikingly similar VH and VL gene-rearrangement sequences among members of the same group [27][28][29][30][31], reflecting the selection and activation of these cases by a restricted set of antigenic epitopes [18]. …”