The chronic lymphocytic leukemia (CLL) immunoglobulin repertoire is uniquely characterized by the presence of stereotyped B-cell receptors (BCRs). A major BCR stereotype in CLL is shared by immunoglobulin G-switched cases utilizing the immunoglobulin heavy-chain variable 4-34 (IGHV4-34) gene. Increased titers of IGHV4-34 antibodies are detected in selective clinical conditions, including infection by B-cell lymphotropic viruses, particularly Epstein-Barr virus (EBV) and cytomegalovirus (CMV). In this context, we sought evidence for persistent activation by EBV and CMV in CLL cases expressing the IGHV4-34 gene. The study group included 93 CLL cases with an intentional bias for the IGHV4-34 gene. On the basis of real-time PCR results for CMV/EBV DNA, cases were assigned to three groups: (1) double-negative (59/93); (2) single-positive (CMV-or EBV-positive; 25/93); (3) double-positive (9/93). The doublenegative group was characterized by heterogeneous IGHV gene repertoire. In contrast, a bias for the IGHV4-34 gene was observed in the single-positive group (9/25 cases; 36%). Remarkably, all nine double-positive cases utilized the IGHV4-34 gene; seven of nine cases expressed the major BCR stereotype as described above. In conclusion, our findings indicate that the interactions of CLL progenitor cells expressing distinctive IGHV4-34 BCRs with viral antigens/superantigens might facilitate clonal expansion and, eventually, leukemic transformation. The exact type, timing and location of these interactions remain to be determined.
The frequent occurrence of stereotyped heavy complementarity-determining region 3 (VH CDR3) sequences among unrelated cases with chronic lymphocytic leukemia (CLL) is widely taken as evidence for antigen selection. Stereotyped VH CDR3 sequences are often defined by the selective association of certain immunoglobulin heavy diversity (IGHD) genes in specific reading frames with certain immunoglobulin heavy joining (IGHJ ) genes. To gain insight into the mechanisms underlying VH CDR3 restrictions and also determine the developmental stage when restrictions in VH CDR3 are imposed, we analyzed partial IGHD-IGHJ rearrangements (D-J) in 829 CLL cases and compared the productively rearranged D-J joints (that is, in-frame junctions without junctional stop codons) to (a) the productive immunoglobulin heavy variable (
2346 Poster Board II-323 A strong sequence-based evidence supporting a role for antigen in the development of CLL is the existence of subsets of patients with stereotyped heavy complementarity-determining region 3 (HCDR3) sequences. Stereotyped HCDR3s are often defined by the selective association of certain IGHD genes in specific reading frames (RF) with certain IGHJ genes, especially IGHJ6. To gain insight into the mechanisms shaping the IG repertoire and also determine the developmental stage when restrictions in HCDR3 are imposed, we investigated the molecular features of incomplete IGHD-IGHJ rearrangements (IDJR) in a series of 830 patients with CLL. IDJRs were detected in 272/830 cases (32.7%). No associations were identified between the occurrence of IDJRs and IGHV gene usage or mutational status in the complete IGHV-D-J rearrangement from the coding IGH allele. A trend for higher IDJR frequency was evident, however, in certain subsets with stereotyped HCDR3s, in particular subset #1 (IGHV1-5-7/IGHD6-19/IGHJ4; 13/33 cases, 40%), #7 (IGHV1-69/IGHD3-3/IGHJ6; 10/21 cases, 48%) and #8 (IGHV4-39/IGHD6-13/IGHJ5; 5/12 cases, 41%). Sequence analysis of the IDJRs revealed: (i) increased frequency of IGHD2 subgroup genes (115/238 cases, 48%), especially IGHD2-2; (ii) equal distribution of the three RFs of the IGHD genes; (iii) increased recombination frequency between 5`genes of the IGHD cluster and 3` genes of the IGHJ cluster, suggestive of secondary rearrangements on the same allele. Overall, 205/238 (86%) IDJRs were considered as potentially functional (PF), since they did not carry a stop codon at the IGHD-J junction. Of note, 26/28 (93%) IDJRs detected in cases from subsets #1, 7 and 8 could be assigned to the PF category. In the group of CLL cases carrying PF IDJRs, comparison of the IGHD gene repertoire in IDJRs vs. complete, expressed IGHV-D-J rearrangements (CE-VDJRs) revealed: (i) statistically significant (p<0.001) selection of the IGHD3-3 and IGHD6-19 genes in RF2 and RF3, respectively, among CE-VDJRs (especially those assigned to subsets #7 and #1, respectively); (ii) preferential usage of RFs encoding for hydrophilic peptides among CE-VDJRs. At a subsequent stage, we compared the repertoire of the IDJRs from the CLL cohort to that of 174 IDJRs obtained from patients with pre-B acute lymphoblastic leukemia (ALL). Except for higher frequency of (i) the IGHD7-27 and IGHJ6 genes and (ii) IGHD-IGHD gene fusions in pre-B ALL, the overall configuration of IDJRs did not differ significantly in CLL vs. pre-B ALL. In conclusion, these results document that the early stages of IG gene rearrangements in pre-B ALL and CLL do not show intrinsic, disease-specific differences. The detailed molecular characterization and comparison of the IGHD and IGHJ gene repertoires in IDJRs vs. CE-VDJRs in CLL provides further support for the notion that CLL development is not stochastic but directed by selection operating at the IG protein level. Disclosures: No relevant conflicts of interest to declare.
Eugenia Tsakou, Andreas Agathagelidis, Myriam Boudjoghra, Thorsten Raff, Antonis Dagklis, Maria Chatzouli, Tatjana Smilevska, George Bourikas, Helene Merle-Beral, Eleni Manioudaki-Kavallieratou, Achilles Anagnostopoulos, Monika Bru.ggemann, Frederic Davi, Kostas Stamatopoulos, and Chrysoula Belessi. (2012) Partial versus Productive Immunoglobulin Heavy Locus Rearrangements in Chronic Lymphocytic Leukemia: Implications for B-Cell Receptor Stereotypy. Mol. Med. 2012 Feb 10;18:138–45.
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