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

Blood. 2011 Sep 15;118(11):3088-95. doi: 10.1182/blood-2011-03-343434. Epub 2011 Jul 26.

Abstract

We examined 807 productive IGHV-IGHD-IGHJ gene rearrangements from mantle cell lymphoma (MCL) cases, by far the largest series to date. The IGHV gene repertoire was remarkably biased, with IGHV3-21, IGHV4-34, IGHV1-8, and IGHV3-23 accounting for 46.3% of the cohort. Eighty-four of 807 (10.4%) cases, mainly using the IGHV3-21 and IGHV4-34 genes, were found to bear stereotyped heavy complementarity-determining region 3 (VH CDR3) sequences and were placed in 38 clusters. Notably, the MCL stereotypes were distinct from those reported for chronic lymphocytic leukemia. Based on somatic hypermutation (SHM) status, 238/807 sequences (29.5%) carried IGHV genes with 100% germ line identity; the remainder (569/807; 70.5%) exhibited different SHM impact, ranging from minimal (in most cases) to pronounced. Shared replacement mutations across the IGHV gene were identified for certain subgroups, especially those using IGHV3-21, IGHV1-8, and IGHV3-23. Comparison with other entities, in particular CLL, revealed that several of these mutations were "MCL-biased." In conclusion, MCL is characterized by a highly restricted immunoglobulin gene repertoire with stereotyped VH CDR3s and very precise SHM targeting, strongly implying a role for antigen-driven selection of the clonogenic progenitors. Hence, an antigen-driven origin of MCL could be envisaged, at least for subsets of cases.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cluster Analysis
  • Cohort Studies
  • Epitopes / genetics*
  • Epitopes / physiology
  • Gene Rearrangement, B-Lymphocyte, Heavy Chain* / genetics
  • Gene Rearrangement, B-Lymphocyte, Heavy Chain* / physiology
  • Genes, Immunoglobulin / genetics
  • Genes, Immunoglobulin / physiology
  • Humans
  • Immunogenetics* / methods
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Variable Region / genetics
  • Lymphoma, Mantle-Cell / etiology*
  • Lymphoma, Mantle-Cell / genetics
  • Lymphoma, Mantle-Cell / immunology*
  • Molecular Sequence Data

Substances

  • Epitopes
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Variable Region