Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors.
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 double-negative 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.
Kostareli
E
E
School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Hadzidimitriou
A
A
Stavroyianni
N
N
Darzentas
N
N
Athanasiadou
A
A
Gounari
M
M
Bikos
V
V
Agathagelidis
A
A
Touloumenidou
T
T
Zorbas
I
I
Kouvatsi
A
A
Laoutaris
N
N
Fassas
A
A
Anagnostopoulos
A
A
Belessi
C
C
Stamatopoulos
K
K
D000368:Aged; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D016022:Case-Control Studies; D015331:Cohort Studies; D003587:Cytomegalovirus / Q000502:physiology*; D018450:Disease Progression; D005260:Female; D016679:Genome, Viral; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000821:virology*; D008297:Male; D008875:Middle Aged; D011947:Receptors, Antigen, B-Cell / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027041:Somatic Hypermutation, Immunoglobulin; D013997:Time Factors; D014775:Virus Activation
D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell