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

Anastasia Hadzidimitriou, Andreas Agathangelidis, Nikos Darzentas, Fiona Murray, Marie Helene Delfau-Larue, Lone Bredo Pedersen, Alba Navarro Lopez, Antonis Dagklis, Paul Rombout, Kheira Beldjord, Arne Kolstad, Martin H. Dreyling, Achilles Anagnostopoulos, Athanasios Tsaftaris, Penelope Mavragani-Tsipidou, Andreas Rosenwald, Maurilio Ponzoni, Patricia Groenen, Paolo Ghia, Birgitta Sander & 7 others Theodora Papadaki, Elias Campo, Christian Geisler, Richard Rosenquist, Frederic Davi, Christiane Pott, Kostas Stamatopoulos

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)3088-3095
Number of pages8
JournalBlood
Volume118
Issue number11
DOIs
Publication statusPublished - Sep 15 2011

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Mantle-Cell Lymphoma
Immunogenetics
Genes
Antigens
Complementarity Determining Regions
Immunoglobulin Genes
Mutation
Gene Rearrangement
B-Cell Chronic Lymphocytic Leukemia
Germ Cells
Immunoglobulins

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Hadzidimitriou, A., Agathangelidis, A., Darzentas, N., Murray, F., Delfau-Larue, M. H., Pedersen, L. B., ... Stamatopoulos, K. (2011). Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases. Blood, 118(11), 3088-3095. https://doi.org/10.1182/blood-2011-03-343434

Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases. / Hadzidimitriou, Anastasia; Agathangelidis, Andreas; Darzentas, Nikos; Murray, Fiona; Delfau-Larue, Marie Helene; Pedersen, Lone Bredo; Lopez, Alba Navarro; Dagklis, Antonis; Rombout, Paul; Beldjord, Kheira; Kolstad, Arne; Dreyling, Martin H.; Anagnostopoulos, Achilles; Tsaftaris, Athanasios; Mavragani-Tsipidou, Penelope; Rosenwald, Andreas; Ponzoni, Maurilio; Groenen, Patricia; Ghia, Paolo; Sander, Birgitta; Papadaki, Theodora; Campo, Elias; Geisler, Christian; Rosenquist, Richard; Davi, Frederic; Pott, Christiane; Stamatopoulos, Kostas.

In: Blood, Vol. 118, No. 11, 15.09.2011, p. 3088-3095.

Research output: Contribution to journalArticle

Hadzidimitriou, A, Agathangelidis, A, Darzentas, N, Murray, F, Delfau-Larue, MH, Pedersen, LB, Lopez, AN, Dagklis, A, Rombout, P, Beldjord, K, Kolstad, A, Dreyling, MH, Anagnostopoulos, A, Tsaftaris, A, Mavragani-Tsipidou, P, Rosenwald, A, Ponzoni, M, Groenen, P, Ghia, P, Sander, B, Papadaki, T, Campo, E, Geisler, C, Rosenquist, R, Davi, F, Pott, C & Stamatopoulos, K 2011, 'Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases', Blood, vol. 118, no. 11, pp. 3088-3095. https://doi.org/10.1182/blood-2011-03-343434
Hadzidimitriou, Anastasia ; Agathangelidis, Andreas ; Darzentas, Nikos ; Murray, Fiona ; Delfau-Larue, Marie Helene ; Pedersen, Lone Bredo ; Lopez, Alba Navarro ; Dagklis, Antonis ; Rombout, Paul ; Beldjord, Kheira ; Kolstad, Arne ; Dreyling, Martin H. ; Anagnostopoulos, Achilles ; Tsaftaris, Athanasios ; Mavragani-Tsipidou, Penelope ; Rosenwald, Andreas ; Ponzoni, Maurilio ; Groenen, Patricia ; Ghia, Paolo ; Sander, Birgitta ; Papadaki, Theodora ; Campo, Elias ; Geisler, Christian ; Rosenquist, Richard ; Davi, Frederic ; Pott, Christiane ; Stamatopoulos, Kostas. / Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases. In: Blood. 2011 ; Vol. 118, No. 11. pp. 3088-3095.
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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.",
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AU - Hadzidimitriou, Anastasia

AU - Agathangelidis, Andreas

AU - Darzentas, Nikos

AU - Murray, Fiona

AU - Delfau-Larue, Marie Helene

AU - Pedersen, Lone Bredo

AU - Lopez, Alba Navarro

AU - Dagklis, Antonis

AU - Rombout, Paul

AU - Beldjord, Kheira

AU - Kolstad, Arne

AU - Dreyling, Martin H.

AU - Anagnostopoulos, Achilles

AU - Tsaftaris, Athanasios

AU - Mavragani-Tsipidou, Penelope

AU - Rosenwald, Andreas

AU - Ponzoni, Maurilio

AU - Groenen, Patricia

AU - Ghia, Paolo

AU - Sander, Birgitta

AU - Papadaki, Theodora

AU - Campo, Elias

AU - Geisler, Christian

AU - Rosenquist, Richard

AU - Davi, Frederic

AU - Pott, Christiane

AU - Stamatopoulos, Kostas

PY - 2011/9/15

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N2 - 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.

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