IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma.
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 IDH2(R172) mutations demonstrated a distinct gene expression signature characterized by downregulation of genes associated with TH1 differentiation (eg, STAT1 and IFNG) and a striking enrichment of an interleukin 12-induced gene signature. Ectopic expression of IDH2(R172K) in the Jurkat cell line and CD4(+) T cells led to markedly increased levels of 2-hydroxyglutarate, histone-3 lysine methylation, and 5-methylcytosine and a decrease of 5-hydroxymethylcytosine. Correspondingly, clinical samples with IDH2 mutations 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.
Shandong University School of Medicine, Jinan, People's Republic of China China; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE; Department of Pathology, City of Hope National Medical Center, Duarte, CA;
Chao
C
Wang
Department of Pathology, City of Hope National Medical Center, Duarte, CA;
Timothy W
TW
McKeithan
Department of Pathology, City of Hope National Medical Center, Duarte, CA;
Qiang
Q
Gong
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE;
Weiwei
W
Zhang
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE;
Alyssa
A
Bouska
Institute of Pathology, and Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany;
Andreas
A
Rosenwald
Department of Pathology and Laboratory Medicine, BC Cancer Agency, Centre for Lymphoid Cancers and the University of British Columbia, Vancouver, BC, Canada;
Randy D
RD
Gascoyne
Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, CA;
Xiwei
X
Wu
Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, CA;
Jinhui
J
Wang
Department of Environmental Agricultural and Occupational Health College of Public Health and.
Zahid
Z
Muhammad
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE; Department of Pathology, City of Hope National Medical Center, Duarte, CA;
Bei
B
Jiang
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE; Department of Pathology, City of Hope National Medical Center, Duarte, CA;
Joseph
J
Rohr
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE;
Andrew
A
Cannon
Department of Pathology and Laboratory Medicine, BC Cancer Agency, Centre for Lymphoid Cancers and the University of British Columbia, Vancouver, BC, Canada;
Christian
C
Steidl
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE;
Kai
K
Fu
Department of Pathology, City of Hope National Medical Center, Duarte, CA;
Yuping
Y
Li
Department of Pathology and Laboratory Medicine, BC Cancer Agency, Centre for Lymphoid Cancers and the University of British Columbia, Vancouver, BC, Canada;
Stacy
S
Hung
Department of Pathology, City of Hope National Medical Center, Duarte, CA;
Dennis D
DD
Weisenburger
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE;
Timothy C
TC
Greiner
Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE;
Lynette
L
Smith
Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany;
German
G
Ott
Department of Environmental Agricultural and Occupational Health College of Public Health and.
Eleanor G
EG
Rogan
Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; and.
Louis M
LM
Staudt
Department of Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE.
Julie
J
Vose
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE;
Javeed
J
Iqbal
Department of Pathology, City of Hope National Medical Center, Duarte, CA;
Wing C
WC
Chan
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D015331:Cohort Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007119:Immunoblastic Lymphadenopathy / Q000145:classification* / Q000235:genetics / Q000473:pathology; D007124:Immunoenzyme Techniques; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D016399:Lymphoma, T-Cell / Q000145:classification* / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis
D014408:Biomarkers, Tumor; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase