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Prepublished online as a Blood First Edition Paper on March 13, 2003; DOI 10.1182/blood-2002-11-3479.
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Blood, 15 May 2003, Vol. 101, No. 10, pp. 4047-4054
NEOPLASIA
Mutated VH genes and preferential VH3-21
use define new subsets of mantle cell lymphoma
Sarah H. Walsh,
Mia Thorsélius,
Anna Johnson,
Ola Söderberg,
Mats Jerkeman,
Erik Björck,
Inger Eriksson,
Ulf Thunberg,
Ola Landgren,
Mats Ehinger,
Eva Löfvenberg,
Kristina Wallman,
Gunilla Enblad,
Birgitta Sander,
Anna Porwit-MacDonald,
Michael Dictor,
Tor Olofsson,
Christer Sundström,
Göran Roos, and
Richard Rosenquist
From the Departments of Genetics and Pathology and of
Oncology, Radiology and Clinical Immunology, Uppsala University;
Departments of Oncology, Pathology, and Hematology, Lund University
Hospital; Department of Medical Biosciences, Pathology, Umeå
University; Departments of Medicine and of Microbiology, Pathology and
Immunology, Division of Pathology, Karolinska Institutet at Huddinge
University Hospital, Stockholm; Department of Medicine, Falun Hospital;
and the Departments of Molecular Medicine, Hematology, and Pathology,
Karolinska Hospital and Institutet, Stockholm, Sweden.
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 use of
certain VH genes. To assess the prognostic impact of these new findings, we performed VH gene analysis of 110 patients, revealing that 18 (16%) patients had mutated and 92 (84%)
patients had unmutated VH genes. Because 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; results showed that the
unrearranged VH gene was identical to the published
sequence. These data confirm that the base pair substitutions within
the rearranged VH genes represent hypermutations, and
indicate germinal center exposure. However, VH gene
mutation status did not correlate with prognosis because there was no
difference in clinical outcome between the unmutated and mutated
groups. The most frequently used 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
use of the V 3-19 gene. VH3-21+
patients had longer median survival than the remaining patients (53 vs
34 months; P = .03), but they tended to be younger at
diagnosis. The combined use 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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