Journal
BLOOD
Volume 126, Issue 15, Pages 1741-1752Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-05-644591
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Funding
- Lymphoma Research Foundation [F-263549]
- Leukemia and Lymphoma Society [6129-14]
- University of Nebraska Medical Center Clinical-Translational Research Scholars Program
- National Institutes of Health
- National Cancer Institute Eppley Cancer Center [P30CA036727]
- City of Hope Cancer Center [P30 CA033572]
- Specialized Programs of Research Excellence [1 P50 CA136411-01 01A1 PP-4]
- Chinese Scholarship Council
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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 down-regulation of genes associated with T-H1 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 andCD4(+) 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 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.
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