IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma

Chao Wang, Timothy W. McKeithan, Qiang Gong, Weiwei Zhang, Alyssa Bouska, Andreas Rosenwald, Randy D. Gascoyne, Xiwei Wu, Jinhui Wang, Muhammad Zahid, Bei Jiang, Joseph Rohr, Andrew Cannon, Christian Steidl, Kai Fu, Yuping Li, Stacy Hung, Dennis D. Weisenburger, Timothy Charles Greiner, Lynette M SmithGerman Ott, Eleanor G Rogan, Louis M. Staudt, Julie Marie Vose, Javeed Iqbal, Wing C. Chan

Research output: Contribution to journalArticle

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Abstract

Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma (PTCL) with a poor prognosis. We performed targeted resequencing on 92 cases of PTCL and identified frequent mutations affecting RHOA, TET2, DNMT3A, and isocitrate dehydrogenase 2 (IDH2). Although IDH2 mutations are largely confined to AITL, mutations of the other 3 can be found in other types of PTCL, although at lower frequencies. These findings indicate a key role of epigenetic regulation in the pathogenesis of AITL. However, the epigenetic alterations induced by these mutations and their role in AITL pathogenesis are still largely unknown. We correlated mutational status with gene expression and global DNA methylation changes in AITL. Strikingly, AITL cases with IDH2R172 mutations demonstrated a distinct gene expression signature characterized by down regulation of genes associated with TH1 differentiation (eg,STAT1 and IFNG) and a striking enrichment of an interleukin 12-induced gene signature. Ectopic expression of IDH2R172K in the Jurkat cell line and CD4+T cells led to markedly increased levels of 2-hydroxyglutarate, histone-3 lysinemethylation, and 5-methylcytosine and a decrease of 5-hydroxymethylcytosine. Correspondingly, clinical samples with IDH2mutations displayed a prominent increase in H3K27me3 and DNA hypermethylation of gene promoters. Integrative analysis of gene expression and promoter methylation revealed recurrently hypermethylated genes involved in T-cell receptor signaling and T-cell differentiation that likely contribute to lymphomagenesis in AITL.

Original languageEnglish (US)
Pages (from-to)1741-1752
Number of pages12
JournalBlood
Volume126
Issue number15
DOIs
StatePublished - Oct 8 2015

Fingerprint

T-cells
T-Cell Lymphoma
Mutation
Peripheral T-Cell Lymphoma
Isocitrate Dehydrogenase
Epigenomics
Genes
Gene expression
5-Methylcytosine
T-Lymphocytes
Gene Expression
Jurkat Cells
DNA Methylation
Interleukin-12
T-Cell Antigen Receptor
Transcriptome
Histones
Methylation
Cell Differentiation
Down-Regulation

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Wang, C., McKeithan, T. W., Gong, Q., Zhang, W., Bouska, A., Rosenwald, A., ... Chan, W. C. (2015). IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma. Blood, 126(15), 1741-1752. https://doi.org/10.1182/blood-2015-05-644591

IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma. / Wang, Chao; McKeithan, Timothy W.; Gong, Qiang; Zhang, Weiwei; Bouska, Alyssa; Rosenwald, Andreas; Gascoyne, Randy D.; Wu, Xiwei; Wang, Jinhui; Zahid, Muhammad; Jiang, Bei; Rohr, Joseph; Cannon, Andrew; Steidl, Christian; Fu, Kai; Li, Yuping; Hung, Stacy; Weisenburger, Dennis D.; Greiner, Timothy Charles; Smith, Lynette M; Ott, German; Rogan, Eleanor G; Staudt, Louis M.; Vose, Julie Marie; Iqbal, Javeed; Chan, Wing C.

In: Blood, Vol. 126, No. 15, 08.10.2015, p. 1741-1752.

Research output: Contribution to journalArticle

Wang, C, McKeithan, TW, Gong, Q, Zhang, W, Bouska, A, Rosenwald, A, Gascoyne, RD, Wu, X, Wang, J, Zahid, M, Jiang, B, Rohr, J, Cannon, A, Steidl, C, Fu, K, Li, Y, Hung, S, Weisenburger, DD, Greiner, TC, Smith, LM, Ott, G, Rogan, EG, Staudt, LM, Vose, JM, Iqbal, J & Chan, WC 2015, 'IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma', Blood, vol. 126, no. 15, pp. 1741-1752. https://doi.org/10.1182/blood-2015-05-644591
Wang, Chao ; McKeithan, Timothy W. ; Gong, Qiang ; Zhang, Weiwei ; Bouska, Alyssa ; Rosenwald, Andreas ; Gascoyne, Randy D. ; Wu, Xiwei ; Wang, Jinhui ; Zahid, Muhammad ; Jiang, Bei ; Rohr, Joseph ; Cannon, Andrew ; Steidl, Christian ; Fu, Kai ; Li, Yuping ; Hung, Stacy ; Weisenburger, Dennis D. ; Greiner, Timothy Charles ; Smith, Lynette M ; Ott, German ; Rogan, Eleanor G ; Staudt, Louis M. ; Vose, Julie Marie ; Iqbal, Javeed ; Chan, Wing C. / IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma. In: Blood. 2015 ; Vol. 126, No. 15. pp. 1741-1752.
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abstract = "Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma (PTCL) with a poor prognosis. We performed targeted resequencing on 92 cases of PTCL and identified frequent mutations affecting RHOA, TET2, DNMT3A, and isocitrate dehydrogenase 2 (IDH2). Although IDH2 mutations are largely confined to AITL, mutations of the other 3 can be found in other types of PTCL, although at lower frequencies. These findings indicate a key role of epigenetic regulation in the pathogenesis of AITL. However, the epigenetic alterations induced by these mutations and their role in AITL pathogenesis are still largely unknown. We correlated mutational status with gene expression and global DNA methylation changes in AITL. Strikingly, AITL cases with IDH2R172 mutations demonstrated a distinct gene expression signature characterized by down regulation of genes associated with TH1 differentiation (eg,STAT1 and IFNG) and a striking enrichment of an interleukin 12-induced gene signature. Ectopic expression of IDH2R172K in the Jurkat cell line and CD4+T cells led to markedly increased levels of 2-hydroxyglutarate, histone-3 lysinemethylation, and 5-methylcytosine and a decrease of 5-hydroxymethylcytosine. Correspondingly, clinical samples with IDH2mutations displayed a prominent increase in H3K27me3 and DNA hypermethylation of gene promoters. Integrative analysis of gene expression and promoter methylation revealed recurrently hypermethylated genes involved in T-cell receptor signaling and T-cell differentiation that likely contribute to lymphomagenesis in AITL.",
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AU - Wang, Chao

AU - McKeithan, Timothy W.

AU - Gong, Qiang

AU - Zhang, Weiwei

AU - Bouska, Alyssa

AU - Rosenwald, Andreas

AU - Gascoyne, Randy D.

AU - Wu, Xiwei

AU - Wang, Jinhui

AU - Zahid, Muhammad

AU - Jiang, Bei

AU - Rohr, Joseph

AU - Cannon, Andrew

AU - Steidl, Christian

AU - Fu, Kai

AU - Li, Yuping

AU - Hung, Stacy

AU - Weisenburger, Dennis D.

AU - Greiner, Timothy Charles

AU - Smith, Lynette M

AU - Ott, German

AU - Rogan, Eleanor G

AU - Staudt, Louis M.

AU - Vose, Julie Marie

AU - Iqbal, Javeed

AU - Chan, Wing C.

PY - 2015/10/8

Y1 - 2015/10/8

N2 - Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma (PTCL) with a poor prognosis. We performed targeted resequencing on 92 cases of PTCL and identified frequent mutations affecting RHOA, TET2, DNMT3A, and isocitrate dehydrogenase 2 (IDH2). Although IDH2 mutations are largely confined to AITL, mutations of the other 3 can be found in other types of PTCL, although at lower frequencies. These findings indicate a key role of epigenetic regulation in the pathogenesis of AITL. However, the epigenetic alterations induced by these mutations and their role in AITL pathogenesis are still largely unknown. We correlated mutational status with gene expression and global DNA methylation changes in AITL. Strikingly, AITL cases with IDH2R172 mutations demonstrated a distinct gene expression signature characterized by down regulation of genes associated with TH1 differentiation (eg,STAT1 and IFNG) and a striking enrichment of an interleukin 12-induced gene signature. Ectopic expression of IDH2R172K in the Jurkat cell line and CD4+T cells led to markedly increased levels of 2-hydroxyglutarate, histone-3 lysinemethylation, and 5-methylcytosine and a decrease of 5-hydroxymethylcytosine. Correspondingly, clinical samples with IDH2mutations displayed a prominent increase in H3K27me3 and DNA hypermethylation of gene promoters. Integrative analysis of gene expression and promoter methylation revealed recurrently hypermethylated genes involved in T-cell receptor signaling and T-cell differentiation that likely contribute to lymphomagenesis in AITL.

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