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Abstract: Mantle cell lymphoma (MCL) is considered to derive from naïve, pregerminal center (GC) CD5+ B-cells. However, the cell of origin has been questioned in recent studies that showed somatic hypermutations in the immunoglobulin (Ig) variable heavy chain (V H ) genes in subsets of MCL. To clarify this issue, we analyzed the IgV H genes for the presence of somatic hypermutations in 51 MCL cases. Twenty percent of the MCL cases displayed somatically mutated V H genes (defined as >2% mutated), whereas 80% showed unmutated V H genes. This finding suggests that MCL is a genetically heterogeneous disease, with the majority of cases originating from unmutated pre-GC B-cells and a subset deriving from more mature B-cells which have been exposed to the GC environment and have undergone somatic hypermutation. A biased V H gene usage has been demonstrated in several B-cell malignancies; however, this has not yet been investigated in MCL, although V H 4-34 overusage has been indicated by small studies. Interestingly, we found a restricted usage of three individual V H genes in our MCL material; V H 4-34 (22%), V H 3-21 (16%) and V H 5-51 (12%). This novel finding of preferential V H gene usage in half of the MCL cases may suggest an antigen driven process occurring in B-cells expressing specific V H genes, thus implicating that Ig specificity could be involved in mantle cell lymphoma development. [ABSTRACT FROM AUTHOR]