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Prepublished online as a Blood First Edition Paper on March 13, 2003; DOI 10.1182/blood-2002-11-3479.
Submitted November 19, 2002
Accepted February 28, 2003
Mutated VH genes and preferential VH3-21 usage define new subsets of mantle cell lymphoma
Sarah H Walsh, Mia Thorselius, Anna Johnson, Ola Soderberg, Mats Jerkeman, Erik Bjorck, Inger Eriksson, Ulf Thunberg, Ola Landgren, Mats Ehinger, Eva Lofvenberg, Kristina Wallman, Gunilla Enblad, Birgitta Sander, Anna Porwit-MacDonald, Michael Dictor, Tor Olofsson, Christer Sundstrom, Goran Roos, and Richard Rosenquist*
Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden
Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden
Department of Oncology, Lund University Hospital, Lund, Sweden
Department of Molecular Medicine, Karolinska Hospital and Institutet, Stockholm, Sweden
Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden
Department of Hematology, Karolinska Hospital and Institutet, Stockholm, Sweden
Department of Pathology, Lund University Hospital, Lund, Sweden
Department of Medicine, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden
Department of Medicine, Falun Hospital, Falun, Sweden
Department of Microbiology, Pathology and Immunology, Division of Pathology, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden
Department of Pathology, Karolinska Hospital and Institutet, Stockholm, Sweden
Department of Hematology, Lund University Hospital, Lund, Sweden
* Corresponding author; email: richard.rosenquist{at}genpat.uu.se.
Mantle cell lymphoma (MCL) is believed to originate from a naive B-cell. However, we recently demonstrated that a subset of MCL displayed mutated VH genes. We also reported restricted usage of certain VH genes. To assess the prognostic impact of these new findings, we performed VH gene analysis of 110 patients, revealing that 18 patients (16%) had mutated and 92 patients (84%) unmutated VH genes. Since the mutation rate was low in the mutated group (2.2-6.7%), further investigation of the germline VH gene in T-cells from 5 patients with mutated VH genes was carried out, showing that the unrearranged VH gene was identical to the published sequence. This data confirms that the base-pair substitutions within the rearranged VH genes represent hypermutations and indicates germinal center exposure. However, the VH gene mutation status did not correlate to prognosis as there was no difference in clinical outcome between the unmutated and mutated groups. The most frequently utilized VH genes were VH3-21 (21 patients) and VH4-34 (19 patients). A novel finding was that VH3-21+ MCL almost exclusively expressed  light chains and displayed highly restricted usage of the V3-19 gene. The VH3-21+ patients had longer median survival than the remaining patients (53 vs 34 months, p=0.03), but they tended to be younger at diagnosis. The combined usage of VH3-21/V3-19 suggests a possible role for antigen(s) in the pathogenesis of these tumors, and indicates that VH3-21+ patients constitute a new MCL entity.
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