Mutated VH genes and preferential VH3-21 use define new subsets of mantle cell lymphoma.

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Abstract
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 λ light chains and displayed highly restricted use of the Vλ3-19 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/Vλ3-19 suggests a possible role for antigen(s) in the pathogenesis of these tumors and indicates that VH3-21+ patients constitute a new MCL entity.