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Blood, 1 January 2007, Vol. 109, No. 1, pp. 259-270.
Prepublished online as a Blood First Edition Paper on September 19, 2006; DOI 10.1182/blood-2006-03-012948.
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NEOPLASIA
Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: pathogenetic implications and clinical correlations
Kostas Stamatopoulos1,
Chrysoula Belessi2,
Carol Moreno3,
Myriam Boudjograh4,
Giuseppe Guida5,
Tatjana Smilevska1,
Lynda Belhoul4,
Stefania Stella5,
Niki Stavroyianni1,
Marta Crespo3,
Anastasia Hadzidimitriou2,
Laurent Sutton6,
Francesc Bosch3,
Nikolaos Laoutaris2,
Achilles Anagnostopoulos1,
Emili Montserrat3,
Athanasios Fassas1,
Guillaume Dighiero7,
Federico Caligaris-Cappio8,
Hélène Merle-Béral4,
Paolo Ghia8,, and
Frédéric Davi4
1 Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece;
2 Hematology Department, Nikea General Hospital, Athens, Greece;
3 Institute of Hematology and Oncology and Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain;
4 Laboratory of Hematology and Université Pierre et Marie Curie, Hôpital Pitié-Salpètrière, Paris, France;
5 Institute for Cancer Research and Treatment, IRCC; Candiolo e Ospedale Mauriziano "Umberto I," Torino, Italy;
6 Department of Clinical Hematology, Hôpital Victor Dupouy, Argenteuil, France;
7 Unité d'Immuno-Hématologie et d'Hématopathologie, Institut Pasteur, Paris, France; and
8 Università Vita-Salute, San Raffaele and Istituto Scientifico San Raffaele, Milano, Italy
The chronic lymphocytic leukemia (CLL) immunoglobulin repertoire is biased and characterized by the existence of subsets of cases with closely homologous ("stereotyped") complementarity-determining region 3 (CDR3) sequences. In the present series, 201 (21.9%) of 916 patients with CLL expressed IGHV genes that belonged to 1 of 48 different subsets of sequences with stereotyped heavy chain (H) CDR3. Twenty-six subsets comprised 3 or more sequences and were considered "confirmed." The remaining subsets comprised pairs of sequences and were considered "potential"; public database CLL sequences were found to be members of 9 of 22 "potential" subsets, thereby allowing us to consider them also "confirmed." The chance of belonging to a subset exceeded 35% for unmutated or selected IGHV genes (eg, IGHV1-69/3-21/4-39). Comparison to non-CLL public database sequences showed that HCDR3 restriction is "CLL-related." CLL cases with selected stereotyped immunoglobulins (IGs) were also found to share unique biologic and clinical features. In particular, cases expressing stereotyped IGHV4-39/IGKV1-39-1D-39 and IGHV4-34/IGKV2-30 were always IgG-switched. In addition, IGHV4-34/IGKV2-30 patients were younger and followed a strikingly indolent disease, contrasting other patients (eg, those expressing IGHV3-21/IGLV3-21) who experienced an aggressive disease, regardless of IGHV mutations. These findings suggest that a particular antigen-binding site can be critical in determining the clinical features and outcome for at least some CLL patients.

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