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 Prepublished online as a Blood First Edition Paper on February 13, 2003; DOI 10.1182/blood-2002-11-3485.

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Blood, 15 June 2003, Vol. 101, No. 12, pp. 4952-4957

NEOPLASIA

Chronic lymphocytic leukemias utilizing the VH3-21 gene display highly restricted V{lambda}2-14 gene use and homologous CDR3s: implicating recognition of a common antigen epitope

Gerard Tobin, Ulf Thunberg, Anna Johnson, Inger Eriksson, Ola Söderberg, Karin Karlsson, Mats Merup, Gunnar Juliusson, Juhani Vilpo, Gunilla Enblad, Christer Sundström, Göran Roos, and Richard Rosenquist

From the Departments of Genetics and Pathology, and Oncology, Radiology and Clinical Immunology, Uppsala University, Sweden; the Department of Medical Biosciences, Pathology, Umeå University, Sweden; the Department of Hematology, Linköping University Hospital, Sweden; the Department of Hematology, Huddinge University Hospital, Sweden; and the Department of Clinical Chemistry, Tampere University Hospital and Helsinki University Central Hospital (Jorvi Hospital), Finland.

The immunoglobulin variable heavy chain (IgVH) gene mutation status is an important prognostic factor in chronic lymphocytic leukemia (CLL), since cases with mutated VH genes show significantly longer survival than unmutated cases. Recently, we reported a preferential use of the VH3-21 gene in mutated CLL and showed that mutated VH3-21 cases had an inferior overall survival compared with other mutated CLL. In order to further characterize this subset, we performed VH gene analysis in 265 CLL cases and identified 31 VH3-21 cases (11.7%); 21 cases had mutated and 10 cases unmutated VH genes. Regardless of VH gene mutation status, a poor overall survival was found in the VH3-21 cases with a median survival of 83 months. These survival data confirm that VH3-21 cases do not fit into the general prognostic grouping of mutated and unmutated CLL. A large fraction of VH3-21 cases also demonstrated unique features with shorter lengths of the third complementarity determining region (CDR3) and CDR3s with highly homologous amino acid sequences. Furthermore, the VH3-21 cases showed a striking dominance of {lambda} light chain expression, and analysis of the Ig{lambda} gene rearrangements revealed highly restricted use of the V{lambda}2-14/J{lambda}3 genes in the majority of cases. Taken together, our new findings strengthen the suggestion that VH3-21–using cases comprise a new CLL entity, irrespective of VH gene mutation status, and implicate that a common antigen epitope, perhaps of pathogenic significance, is recognized by the highly homologous VH3-21/V{lambda}2-14 Ig molecules expressed in individual tumors.


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