They include the V600E BRAF mutation in hairy cell leukemia, the L265P MYD88 mutation in Waldenström macroglobulinemia, the G17VRHOA mutation in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified, and the Y640F//D661Y/V/H/I//N647I STAT3 mutations in T-cell large granular lymphocytic leukemia.
Among these six candidate genes, only IDH2 and RHOA mutations were significantly more frequent in nodal subtypes, angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) (P = .002 and <0.001, respectively).
Herein, to improve the current molecular classification between AITL and PTCL-NOS, we analyzed the transcriptional profiles from 503 PTCLs stratified according to their molecular configuration and integrated them with genomic data of recurrently mutated genes (RHOA <sup>G17V</sup> , TET2, IDH2 <sup>R172</sup> , and DNMT3A) in 53 cases (39 AITLs and 14 PTCL-NOSs) included in the series.
These analyses identified highly recurrent epigenetic factor mutations in TET2, DNMT3A and IDH2 as well as a new highly prevalent RHOA mutation encoding a p.Gly17Val alteration present in 22 of 35 (67%) angioimmunoblastic T cell lymphoma (AITL) samples and in 8 of 44 (18%) PTCL, not otherwise specified (PTCL-NOS) samples.
Recently, a novel recurring somatic mutation in RHOA, encoding p.Gly17Val, was discovered in nearly 70% of AITLs and in a smaller proportion of peripheral T-cell lymphomas, not otherwise specified (PTCL-NOS).
G17VRHOA mutations were identified in 27 of 67 (40.3%) PTCL samples using NGS. ddPCR and PNA-LNA clamp method both detected G17V mutations in 4 samples in addition to those detected with NGS (31 of 67, 46.3%).
IDH2 mutations were identified in approximately 20% of angioimmunoblastic T-cell lymphomas (AITLs), but not in other peripheral T-cell lymphoma entities.
Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma with mutations in genes encoding isocitrate dehydrogenase1 and 2 (IDH1 and IDH2).
Among these six candidate genes, only IDH2 and RHOA mutations were significantly more frequent in nodal subtypes, angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) (P = .002 and <0.001, respectively).
These analyses identified highly recurrent epigenetic factor mutations in TET2, DNMT3A and IDH2 as well as a new highly prevalent RHOA mutation encoding a p.Gly17Val alteration present in 22 of 35 (67%) angioimmunoblastic T cell lymphoma (AITL) samples and in 8 of 44 (18%) PTCL, not otherwise specified (PTCL-NOS) samples.
Recent genetic analysis has identified frequent mutations in ten-eleven translocation 2 (TET2), DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 2 (IDH2) and ras homolog family member A (RHOA) in nodal T-cell lymphomas, including angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified.
Among PTCL-NOS, a heterogeneous group of lymphoma-comprising cases likely to derive from Th follicular (T(FH)) cells similarly to AITL, TET2 mutations were more frequent when PTCL-NOS expressed T(FH) markers and/or had features reminiscent of AITL (58% vs 24%, P = .01).
TET2 loss-of-function mutations are highly frequent in subtypes of T-cell lymphoma that harbor follicular helper T (Tfh)-cell-like features, such as angioimmunoblastic T-cell lymphoma (30-83%) or peripheral T-cell lymphoma, not otherwise specified (10-49%), as well as myeloid malignancies.
PTCL samples with TET2 mutations were more frequently hypermethylated than those without TET2 mutations (PTCL with TET2 mutations vs without mutations: 6/22 vs 0/17).
In addition, we describe new and recurrent, albeit less frequent, genetic defects including mutations in FYN, ATM, B2M and CD58 implicating SRC signaling, impaired DNA damage response and escape from immune surveillance mechanisms in the pathogenesis of PTCL.
These results suggest that both BCL3 and PVRL2 may participate in the pathogenesis of these PTCLs, but further studies should be undertaken to investigate the precise role of these genes.
We found increased transcription of the CD28-responsive genes CD226 and TNFA in cells expressing the T195P mutant in response to CD3 and CD86 co-stimulation and increased downstream activation of NF-κB by both D124V and T195P mutants, suggesting a potential therapeutic target in CD28-mutated PTCLs.
Recently, a novel recurring somatic mutation in RHOA, encoding p.Gly17Val, was discovered in nearly 70% of AITLs and in a smaller proportion of peripheral T-cell lymphomas, not otherwise specified (PTCL-NOS).
PTCL, not otherwise specified (PTCL, NOS), the largest PTCL category, which is derived from activated CD4+ (or CD8+) T cells, is markedly heterogeneous, including at the molecular level.
Although the outcome for patients with anaplastic large cell lymphoma (ALCL), particularly anaplastic lymphoma kinase (ALK)-positive ALCL, is good, other types of PTCLs are associated with a poor prognosis, even with aggressive anthracycline-based chemotherapy.
Rare cases of peripheral T-cell lymphomas with follicular growth pattern (PTCL-F) have been recently reported, and their association with t(5;9)(q33;q22) involving ITK and SYK has been suggested.