TY - JOUR
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 E.
AU - Bernard, Olivier A.
AU - Aoufouchi, Said
AU - Li, Sheng
AU - Shaknovich, Rita
AU - Melnick, Ari M.
N1 - Funding Information:
M.A. Rubin reports receiving a commercial research grant from Janssen, has received honoraria from the speakers bureau of Roche, and is a consultant/advisory board member for ViridBio and Astel-las. R.L. Levine is on the supervisory board of Qiagen and scientific advisory board of Loxo, C4 Therapeutics, and Isoplexis; and is a consultant for and receives research support from Roche and Celgene. A.M. Melnick reports receiving research support from Janssen. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
We thank people from the Epigenomics Core Weill Cornell Medicine (WCM), Genomics Core WCM, Flow Cytometry Core WCM, Laboratory of Comparative Pathology WCM and MSKCC; Edward Holson and Kdac Therapeutics Inc. for the HDAC3 inhibitor; members of the Gustave Roussy Platforms, including Patrick Gonin, Yann Lecluse, Philippe Rameau, and Olivia Bawa; and Daisuke Kita-mura (Tokyo University of Science, Japan) for the kind gift of the 40LB cell line. Research reported in this publication was supported by the Office of the Director of the NIH under Award Number S10OD019986 to Hospital for Special Surgery. P.M. Dominguez is supported by a Lymphoma Research Foundation Postdoctoral Fellowship. H. Ghamlouch is supported by a grant from Fondation de France (No 00067113). O. Elemento is supported by NSF CAREER, LLS SCOR, Hirschl Trust Award, Starr Cancer Consortium I6-A618, NIH 1R01CA19454. M.R. Green is supported by R01 CA201380. O.A. Bernard is supported by the Institut National du Cancer (2013-PLBIO-09, 2016-PLBIO-068 and INCa-DGOS-INSERM 12551), Association Laurette Fugain, and équipe labelisée Ligue Nationale Contre le Cancer. S. Aoufouchi is supported by Comité Val-d’Oise de la Ligue contre le cancer. S. Li is supported by Leukemia Research Foundation Research Grant, The Jackson Laboratory Cancer Center New Investigator Award, and The Jackson Laboratory Director’s Innovation Fund. Research reported in this publication was partially supported by the NCI of the NIH under Award Number P30CA034196. A.M. Melnick is supported by the Chemotherapy Foundation, The Follicular Lymphoma Research Consortium, Leukemia and Lymphoma Society SCOR Grant #7012-16, and the Starr Cancer Consortium. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
PY - 2018/12
Y1 - 2018/12
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.
AB - 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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U2 - 10.1158/2159-8290.CD-18-0657
DO - 10.1158/2159-8290.CD-18-0657
M3 - Article
C2 - 30274972
AN - SCOPUS:85058063303
VL - 8
SP - 1633
EP - 1653
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 12
ER -