Molecular genetic characterization reveals new subsets of mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy, which is believed to originate from naive B-cells in the mantle zone of lymph nodes. Recently, a more diverse cellular origin has been implicated in MCL, since the disease was shown to consist of two subsets based on immunoglobulin heavy-chain variable (IGHV) gene analysis; a major subset with unmutated IGHV genes and a smaller subset (approximately 20 to 30%) displaying mutated IGHV genes. Presence of somatic hypermutation in the 'mutated' subset suggests either exposure to a germinal centre (GC) environment or that somatic hypermutation has been acquired in a non-GC context. Furthermore, a preferential IGHV gene utilization has been revealed in MCL, where IGHV3-21 and IGHV4-34 are the most predominant. MCLs with an IGHV3-21 usage almost exclusively share the same light chain (IGLV3-19) use and this subset is also related to a better prognosis. MCL cases utilising the IGHV3-21 gene display less chromosomal alterations than MCLs using other IGHV genes and in addition, gains in 15q and losses in 9p were not observed in any of these cases. These latter findings are in favour of the hypothesis that IGHV3-21(+) tumours may represent a distinct MCL subentity and that there is a possible role for antigens in MCL development. In this review, we will summarise these recent studies of IG gene rearrangements in MCL as well as molecular cytogenetic characteristics of this malignancy.

Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era

“…Interestingly, the structure of the IGHV3-21 CDR3 region differs between MCL and CLL, suggesting a different antigen specificity of the B-cell receptor (BCR) in these 2 malignancies. 15 Combined, these findings indicate that at least a subset of MCL, similar to CLL, is derived from antigenexperienced B cells. In keeping with this notion is the expression of genes that code for chemokine receptors involved in trafficking after initial B-cell activation.…”

Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases

“…[12][13]17,18 Although certainly of interest, we refrained from exploring potential clinical correlations given the retrospective character of our study and also taking into account that patients were not treated uniformly. Second, perhaps more importantly, on the evidence reported here, the majority of MCL cases indeed carry some level of SHM, which also seems to be distributed in a "disease-biased" manner.…”

“…[12][13][14][15][16][17][18] In all published series, the classification of MCL cases based on SHM status was based on the 2% identity cut-off from the closest IGHV germ line gene, following the example of CLL, where this cut-off proved to be an accurate prognosticator of patient survival. 20 This approach should be viewed with caution for the following reasons.…”

“…[12][13][14][15][16][17] Moreover, there is evidence suggesting potential associations with molecular and clinical features for cases expressing certain IGHV genes (eg, IGHV3-21 and IGHV3-23). 12,13,[16][17][18] All relevant studies consistently showed that in the majority of MCL cases the clonotypic IGHV genes were either unmutated or exhibited a low impact of SHM activity. Based on this and other observations, the cellular origin of MCL was traced to a stage of B-cell development before the transition through the germinal center.…”

“…19p232 Against this, virtually all aforementioned studies have reported the existence of a subset of MCL patients with mutated IGHV genes, variably accounting for from 16%-38% of cases. [12][13][14][15][16][17][18] This poses a conundrum, given the prevailing views about MCL ontogeny. In all studies, assignment to the "mutated" IGHV subset followed the 2% cut-off value for deviation from the closest IGHV germ line gene, which is widely used for prognostication in CLL.…”