IDH2 R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma

Abstract

Key Points• IDH2R172 mutations define a unique subgroup with distinct T FH -like gene expression signatures in AITL.• IDH2 R172 mutations can induce DNA and repressive histone hypermethylation in AITL.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

The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development

“…the G17V residue have been proposed as driver events in PTCL (13,21,22). Among these drivers, IDH2 mutations seem restricted to AITL, whereas TET2, DNMT3A, and RHOA mutations can be found in other PTCL entities as well, although they are enriched in PTCL of T FH origin (12,13,19,23). These findings suggest that epigenetic alteration is a hallmark of malignant transformation in AITL.…”

“…The small population of malignant cells display a T follicular helper (T FH ) cell phenotype, and this population is thought to be the cell of origin for this disease (17). Recently, recurrent mutations in the epigenetic regulators TET2 (18,19), IDH2 (11,12), and DNA (cytosine-5)-methyltransferase 3A (DNMT3A) (20) as well as mutation of Ras homolog family member A (RHOA) at…”

“…Indeed, IDH mutations in glioma are IDH1R132 in more than 90% of cases (10), whereas IDH mutations in AITL are present at IDH2R172 almost exclusively (11)(12)(13)(14).…”

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…This oncometabolite represses H3K and DNA 5-mC demethylation by inhibiting TET2, thus leading to abnormal regulation of gene transcription which potentially promotes lymphomagenesis. This is underpinned by the finding that about 30% of AITL cases possess IDH2 mutations [65,108]. Furthermore, TCR signaling and T-cell differentiation promoting genes are hypermethylated [65].…”

“…This is underpinned by the finding that about 30% of AITL cases possess IDH2 mutations [65,108]. Furthermore, TCR signaling and T-cell differentiation promoting genes are hypermethylated [65]. Interestingly, no IDH1 mutations have been mapped in AITL as yet, and only the IDH2 R172 mutant but not IDH 2 R140 (a frequent mutation in myeloid neoplasms) has been documented.…”