TET2 deficiency causes germinal center hyperplasia, impairs plasma cell differentiation, and promotes b-cell lymphomagenesis

Pilar M. Dominguez, Hussein Ghamlouch, Wojciech Rosikiewicz, Parveen Kumar, Wendy Béguelin, Lorena Fontán, Martín A. Rivas, Patrycja Pawlikowska, Marine Armand, Enguerran Mouly, Miguel Torres-Martin, Ashley S. Doane, María T. Calvo Fernandez, Matt Durant, Veronique Della-Valle, Matt Teater, Luisa Cimmino, Nathalie Droin, Saber Tadros, Samaneh MotanaghAlan H. Shih, Mark A. Rubin, Wayne Tam, Iannis Aifantis, Ross L. Levine, Olivier Elemento, Giorgio Inghirami, Michael R. Green, Maria Figueroa, Olivier A. Bernard, Said Aoufouchi, Sheng Li, Rita Shaknovich, Ari M. Melnick

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

TET2 somatic mutations occur in ∼10% of diffuse large B-cell lymphomas (DLBCL) but are of unknown significance. Herein, we show that TET2 is required for the humoral immune response and is a DLBCL tumor suppressor. TET2 loss of function disrupts transit of B cells through germinal centers (GC), causing GC hyperplasia, impaired class switch recombination, blockade of plasma cell differentiation, and a preneoplastic phenotype. TET2 loss was linked to focal loss of enhancer hydroxymethylation and transcriptional repression of genes that mediate GC exit, such as PRDM1. Notably, these enhancers and genes are also repressed in CREBBP-mutant DLBCLs. Accordingly, TET2 mutation in patients yields a CREBBP-mutant gene-expression signature, CREBBP and TET2 mutations are generally mutually exclusive, and hydroxymethylation loss caused by TET2 deficiency impairs enhancer H3K27 acetylation. Hence, TET2 plays a critical role in the GC reaction, and its loss of function results in lymphomagenesis through failure to activate genes linked to GC exit signals. SIGNIFICANCE: We show that TET2 is required for exit of the GC, B-cell differentiation, and is a tumor suppressor for mature B cells. Loss of TET2 phenocopies CREBBP somatic mutation. These results advocate for sequencing TET2 in patients with lymphoma and for the testing of epigenetic therapies to treat these tumors. Cancer.

Original languageEnglish (US)
Pages (from-to)1633-1653
Number of pages21
JournalCancer Discovery
Volume8
Issue number12
DOIs
StatePublished - Dec 1 2018

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Germinal Center
Plasma Cells
Hyperplasia
Cell Differentiation
Mutation
B-Lymphocytes
Lymphoma, Large B-Cell, Diffuse
Neoplasms
Genes
Acetylation
Humoral Immunity
Transcriptome
Epigenomics
Genetic Recombination
Lymphoma
Phenotype

ASJC Scopus subject areas

  • Oncology

Cite this

Dominguez, P. M., Ghamlouch, H., Rosikiewicz, W., Kumar, P., Béguelin, W., Fontán, L., ... Melnick, A. M. (2018). TET2 deficiency causes germinal center hyperplasia, impairs plasma cell differentiation, and promotes b-cell lymphomagenesis. Cancer Discovery, 8(12), 1633-1653. https://doi.org/10.1158/2159-8290.CD-18-0657

TET2 deficiency causes germinal center hyperplasia, impairs plasma cell differentiation, and promotes b-cell lymphomagenesis. / Dominguez, Pilar M.; Ghamlouch, Hussein; Rosikiewicz, Wojciech; Kumar, Parveen; Béguelin, Wendy; Fontán, Lorena; Rivas, Martín A.; Pawlikowska, Patrycja; Armand, Marine; Mouly, Enguerran; Torres-Martin, Miguel; Doane, Ashley S.; Calvo Fernandez, María T.; Durant, Matt; Della-Valle, Veronique; Teater, Matt; Cimmino, Luisa; Droin, Nathalie; Tadros, Saber; Motanagh, Samaneh; Shih, Alan H.; Rubin, Mark A.; Tam, Wayne; Aifantis, Iannis; Levine, Ross L.; Elemento, Olivier; Inghirami, Giorgio; Green, Michael R.; Figueroa, Maria; Bernard, Olivier A.; Aoufouchi, Said; Li, Sheng; Shaknovich, Rita; Melnick, Ari M.

In: Cancer Discovery, Vol. 8, No. 12, 01.12.2018, p. 1633-1653.

Research output: Contribution to journalArticle

Dominguez, PM, Ghamlouch, H, Rosikiewicz, W, Kumar, P, Béguelin, W, Fontán, L, Rivas, MA, Pawlikowska, P, Armand, M, Mouly, E, Torres-Martin, M, Doane, AS, Calvo Fernandez, MT, Durant, M, Della-Valle, V, Teater, M, Cimmino, L, Droin, N, Tadros, S, Motanagh, S, Shih, AH, Rubin, MA, Tam, W, Aifantis, I, Levine, RL, Elemento, O, Inghirami, G, Green, MR, Figueroa, M, Bernard, OA, Aoufouchi, S, Li, S, Shaknovich, R & Melnick, AM 2018, 'TET2 deficiency causes germinal center hyperplasia, impairs plasma cell differentiation, and promotes b-cell lymphomagenesis', Cancer Discovery, vol. 8, no. 12, pp. 1633-1653. https://doi.org/10.1158/2159-8290.CD-18-0657
Dominguez, Pilar M. ; Ghamlouch, Hussein ; Rosikiewicz, Wojciech ; Kumar, Parveen ; Béguelin, Wendy ; Fontán, Lorena ; Rivas, Martín A. ; Pawlikowska, Patrycja ; Armand, Marine ; Mouly, Enguerran ; Torres-Martin, Miguel ; Doane, Ashley S. ; Calvo Fernandez, María T. ; Durant, Matt ; Della-Valle, Veronique ; Teater, Matt ; Cimmino, Luisa ; Droin, Nathalie ; Tadros, Saber ; Motanagh, Samaneh ; Shih, Alan H. ; Rubin, Mark A. ; Tam, Wayne ; Aifantis, Iannis ; Levine, Ross L. ; Elemento, Olivier ; Inghirami, Giorgio ; Green, Michael R. ; Figueroa, Maria ; Bernard, Olivier A. ; Aoufouchi, Said ; Li, Sheng ; Shaknovich, Rita ; Melnick, Ari M. / TET2 deficiency causes germinal center hyperplasia, impairs plasma cell differentiation, and promotes b-cell lymphomagenesis. In: Cancer Discovery. 2018 ; Vol. 8, No. 12. pp. 1633-1653.
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abstract = "TET2 somatic mutations occur in ∼10{\%} of diffuse large B-cell lymphomas (DLBCL) but are of unknown significance. Herein, we show that TET2 is required for the humoral immune response and is a DLBCL tumor suppressor. TET2 loss of function disrupts transit of B cells through germinal centers (GC), causing GC hyperplasia, impaired class switch recombination, blockade of plasma cell differentiation, and a preneoplastic phenotype. TET2 loss was linked to focal loss of enhancer hydroxymethylation and transcriptional repression of genes that mediate GC exit, such as PRDM1. Notably, these enhancers and genes are also repressed in CREBBP-mutant DLBCLs. Accordingly, TET2 mutation in patients yields a CREBBP-mutant gene-expression signature, CREBBP and TET2 mutations are generally mutually exclusive, and hydroxymethylation loss caused by TET2 deficiency impairs enhancer H3K27 acetylation. Hence, TET2 plays a critical role in the GC reaction, and its loss of function results in lymphomagenesis through failure to activate genes linked to GC exit signals. SIGNIFICANCE: We show that TET2 is required for exit of the GC, B-cell differentiation, and is a tumor suppressor for mature B cells. Loss of TET2 phenocopies CREBBP somatic mutation. These results advocate for sequencing TET2 in patients with lymphoma and for the testing of epigenetic therapies to treat these tumors. Cancer.",
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T1 - TET2 deficiency causes germinal center hyperplasia, impairs plasma cell differentiation, and promotes b-cell lymphomagenesis

AU - Dominguez, Pilar M.

AU - Ghamlouch, Hussein

AU - Rosikiewicz, Wojciech

AU - Kumar, Parveen

AU - Béguelin, Wendy

AU - Fontán, Lorena

AU - Rivas, Martín A.

AU - Pawlikowska, Patrycja

AU - Armand, Marine

AU - Mouly, Enguerran

AU - Torres-Martin, Miguel

AU - Doane, Ashley S.

AU - Calvo Fernandez, María T.

AU - Durant, Matt

AU - Della-Valle, Veronique

AU - Teater, Matt

AU - Cimmino, Luisa

AU - Droin, Nathalie

AU - Tadros, Saber

AU - Motanagh, Samaneh

AU - Shih, Alan H.

AU - Rubin, Mark A.

AU - Tam, Wayne

AU - Aifantis, Iannis

AU - Levine, Ross L.

AU - Elemento, Olivier

AU - Inghirami, Giorgio

AU - Green, Michael R.

AU - Figueroa, Maria

AU - Bernard, Olivier A.

AU - Aoufouchi, Said

AU - Li, Sheng

AU - Shaknovich, Rita

AU - Melnick, Ari M.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - TET2 somatic mutations occur in ∼10% of diffuse large B-cell lymphomas (DLBCL) but are of unknown significance. Herein, we show that TET2 is required for the humoral immune response and is a DLBCL tumor suppressor. TET2 loss of function disrupts transit of B cells through germinal centers (GC), causing GC hyperplasia, impaired class switch recombination, blockade of plasma cell differentiation, and a preneoplastic phenotype. TET2 loss was linked to focal loss of enhancer hydroxymethylation and transcriptional repression of genes that mediate GC exit, such as PRDM1. Notably, these enhancers and genes are also repressed in CREBBP-mutant DLBCLs. Accordingly, TET2 mutation in patients yields a CREBBP-mutant gene-expression signature, CREBBP and TET2 mutations are generally mutually exclusive, and hydroxymethylation loss caused by TET2 deficiency impairs enhancer H3K27 acetylation. Hence, TET2 plays a critical role in the GC reaction, and its loss of function results in lymphomagenesis through failure to activate genes linked to GC exit signals. SIGNIFICANCE: We show that TET2 is required for exit of the GC, B-cell differentiation, and is a tumor suppressor for mature B cells. Loss of TET2 phenocopies CREBBP somatic mutation. These results advocate for sequencing TET2 in patients with lymphoma and for the testing of epigenetic therapies to treat these tumors. Cancer.

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