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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1678-1685.
Prepublished online as a Blood First Edition Paper on October 5, 2004; DOI 10.1182/blood-2004-07-2606.
 Previous Article | Next Article 
Submitted July 9, 2004
Accepted September 30, 2004
Geographical patterns and pathogenetic implications of IGHV gene usage in chronic lymphocytic leukemia: the lesson of the IGHV3-21 gene
Paolo Ghia*, Kostas Stamatopoulos, Chrysoula Belessi, Carol Moreno, Stefania Stella, Giuseppe Guida, Ariane Michel, Marta Crespo, Nikolaos Laoutaris, Emili Montserrat, Achilles Anagnostopoulos, Guillaume Dighiero, Athanasios Fassas, Federico Caligaris-Cappio, and Frederic Davi
Department of Oncological Sciences, University of Torino and Institute for Cancer Research and Treatment, Torino, Italy
Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece
Hematology Department, Nikea General Hospital, Athens, Greece
Hospital Clinic, Institute of Hematology and Oncology and Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Laborary of Hematology and University Paris 6, Hopital Pitie-Salpetriere, Paris, France
Unite d'Immuno-Hematologie et d'Hematopathologie, Institut Pasteur, Paris, France
Department of Oncology, Universita Vita Salute - San Raffaele, Milano, Italy
* Corresponding author; email: paolo.ghia{at}unito.it.
We studied IGHV repertoire and mutational status in 553 CLL patients from the Mediterranean area to gain insight into the potential pathogenetic role of antigenic stimulation. The most commonly represented IGHV genes mirrored the usage of normal B cells, with the exception of IGHV1-18, IGHV3-30.3 and IGHV4-59 that were underrepresented. The IGHV3-21 gene, frequently expressed in Northern European CLL, was present only in 16 cases (2.9%). Based on HCDR3 cluster analysis, IGHV3-21-utilizing cases could be grouped in two subsets of similar frequency. The first one (7/16 cases) carried a similar HCDR3 amino acid sequence (common-HCDR3 subset), virtually identical to the Scandinavian IGHV3-21 CLL. These cases used the IGHJ6 gene; 4/7 were unmutated; 6/7 carried the V 2-14 (IGLV3-21) light chain gene with a similar LCDR3. All expressed CD38 and had a progressive disease. The second subset (9/16) was characterized by heterogeneous HCDR3 rearrangements (non-homogeneous-HCDR3 subset), diverse IGHJ and IGV light chain gene usage, variable IGHV mutational status (5/9 unmutated), variable CD38 expression and variable clinical course (4/9 progressed). The first subset suggests a potential antigenic element rarely encountered in the Mediterranean area, possibly responsible for a negative outcome. The second subset may reflect the physiologic heterogeneity of expression of IGHV3-21 rearrangements in the normal repertoire, and is characterized by a variable clinical outcome.
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