Somatic hypermutation and V_H gene usage in mantle cell lymphoma

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 VH genes, thus implicating that Ig specificity could be involved in mantle cell lymphoma development.

Sequence analysis proves clonal identity in five patients with typical and blastoid mantle cell lymphoma

“…18 Similarly, Pittaluga et al 19 21 Compared to these studies, we found a higher percentage (60%) of mutated cases. This discrepancy may be due to our referral patient population or to the relatively small size of our series, rather than reflecting the biology of MCL cases that subsequently undergo histologic progression.…”

Prognostic impact of p27KIP1 expression in cyclin D1 positive lymphoproliferative disorders

“…20 Several studies have reported the presence of somatic mutations in a subset of MCL. 12,[21][22][23][24][25] Although none of the studies reports a statistically different survival advantage for mutated cases, a study by Orchard et al, 12 demonstrates that t (11;14) lymphocytosis is also heterogeneous with respect to IgV H mutations, with the presence of somatic mutations being restricted to the non-nodal group, and more frequently found among the long-term survivors.…”

Mantle cell lymphomas with clonal immunoglobulin V3–21 gene rearrangements exhibit fewer genomic imbalances than mantle cell lymphomas utilizing other immunoglobulin V genes

“…High-molecular-weight DNA was prepared from fresh frozen tumor tissues using a standard protocol for phenol-chloroform extraction as previously outlined 2 or with the QIAamp DNA Mini Kit (Qiagen, Valencia, CA, USA), according to the recommendations from the manufacturer.…”

“…For the majority of cases, naïve pregerminal center B cells, located in primary lymphoid follicles or the mantle zone of secondary follicles are considered to give rise to the transformed cells. 1,2 Cytogenetically, mantle cell lymphoma is characterized by a reciprocal translocation, t(11;14)(q13;q32), which is found in virtually all cases. 3 Through this rearrangement, CCND1/PRAD-1/BCL1 on chromosome 11 is juxtaposed to the active IGH enhancer on chromosome 14.…”

“…3 Characterization of variable heavy chain (V H ) gene usage has recently been performed in mantle cell lymphoma, revealing that two particular V H gene segments of the immunoglobulin (Ig) locus were preferentially used, namely V H 3-21 (18%) and V H 4-34 (16%). 2,6 Interestingly, the tumor samples with V H 3-21 gene usage almost exclusively expressed lambda light chains, and also in most cases utilized the same V l light chain gene (V l [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. 6 In addition, this group has been shown to have a significantly better prognosis in one report and in other studies displayed a clear tendency towards improved survival compared to mantle cell lymphomas utilizing other V H genes.…”