Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

E Kostareli, A Hadzidimitriou, N Stavroyianni, N Darzentas, A Athanasiadou, M Gounari, V Bikos, A Agathagelidis, T Touloumenidou, I Zorbas, A Kouvatsi, N Laoutaris, A Fassas, A Anagnostopoulos, C Belessi, K Stamatopoulos

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65 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)919-24
Number of pages6
Issue number5
Publication statusPublished - May 2009
Externally publishedYes


  • Aged
  • B-Lymphocytes/immunology
  • Case-Control Studies
  • Cohort Studies
  • Cytomegalovirus/physiology
  • Disease Progression
  • Female
  • Genome, Viral
  • Herpesvirus 4, Human/physiology
  • Humans
  • Immunoglobulin Heavy Chains/genetics
  • Immunoglobulin Variable Region/genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell/genetics
  • Male
  • Middle Aged
  • Receptors, Antigen, B-Cell/genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Somatic Hypermutation, Immunoglobulin
  • Time Factors
  • Virus Activation


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