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 language | English (US) |
|---|---|
| Pages (from-to) | 1633-1653 |
| Number of pages | 21 |
| Journal | Cancer Discovery |
| Volume | 8 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2018 |
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ASJC Scopus subject areas
- Oncology
Cite this
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 journal › Article
}
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
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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85058063303&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058063303&partnerID=8YFLogxK
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 -