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

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

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.

Agathangelidis, Andreas (author)
Darzentas, Nikos (author)
Murray, FionaUppsala universitet,Institutionen för immunologi, genetik och patologi(Swepub:uu)fimur450 (author)
Delfau-Larue, Marie-Helene (author)
Pedersen, Lone Bredo (author)
Navarro Lopez, Alba (author)
Dagklis, Antonis (author)
Rombout, Paul (author)
Beldjord, Kheira (author)
Kolstad, Arne (author)
Dreyling, Martin H. (author)
Anagnostopoulos, Achilles (author)
Tsaftaris, Athanasios (author)
Mavragani-Tsipidou, Penelope (author)
Rosenwald, Andreas (author)
Ponzoni, Maurilio (author)
Groenen, Patricia (author)
Ghia, Paolo (author)
Sander, BirgittaKarolinska Institutet (author)
Papadaki, Theodora (author)
Campo, Elias (author)
Geisler, Christian (author)
Rosenquist, RichardUppsala universitet,Institutionen för immunologi, genetik och patologi(Swepub:uu)richrose (author)
Davi, Frederic (author)
Pott, Christiane (author)
Stamatopoulos, Kostas (author)
Uppsala universitetInstitutionen för immunologi, genetik och patologi (creator_code:org_t)

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