The new biology of PTCL‐NOS and AITL: current status and future clinical impact

Abstract

Summary Peripheral T‐cell lymphomas (PTCL) comprise a heterogeneous group of aggressive lymphoproliferative disorders almost all of which are associated with poor clinical outcomes. Angioimmunoblastic T‐cell lymphoma (AITL) and some peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS) have similarities to normal CD4+ T‐cell subsets in their gene expression profiles. A cell of origin model is, therefore, emerging and is likely to be refined in the future. Follicular helper (Tfh) T cells are now established as the cell of origin of AITL and about 20% of PTCL‐NOS. Sequencing studies have identified recurrent genetic alterations in epigenetic modifiers, T‐cell receptor signalling pathway intermediates or RHOA, most commonly a specific mutation leading to RHOA G17V. While PTCL‐NOS remains a diagnosis of exclusion, advances in genomics have identified subgroups expressing transcription factors TBX 21 (Th1‐like origin) and GATA3 (Th2‐like origin). These findings suggest new biomarkers and new therapeutic avenues including the hypomethylating agent azacytidine, or inhibitors of proximal T‐cell receptor (TCR) signalling and potentially certain monoclonal antibodies. The advances over the past few years, therefore, prompt stratified medicine approaches to test biologically based treatments and determine the clinical utility of the new disease classifications.

Molecular insights into pathogenesis and targeted therapy of peripheral T cell lymphoma

“…Together, alterations of histone modifying genes might represent a distinct biological characteristic. RHOA mutant (G17V), a loss-of-function mutation, has been identified in both AITL (53-71%) and PTCL-NOS (8-18%) [5,19,20]. As discussed above, the presence of RHOA (G17V) mutations in most PTCL-NOS cases correlated with a T FH cell phenotype similar to the phenotype of AITL.…”

“…Recently, it is well known that a proportion (about 20%) of PTCL-NOS, similar to AITL, is derived from T-follicular helper (T FH ) cells. Other cases of PTCL-NOS are derived from the TH1 or TH2 cells, and have similar gene expression profiles to cytotoxic T-cells, respectively [5]. The molecular findings in PTCL-NOS are heterogeneous and show significant overlap with other PTCL subtypes.…”

“…Angioimmunoblastic T-cell lymphoma (AITL), the second most common subtype of PTCL, is derived from the T FH cell, and has a distinct gene expression profile that is different from other PTCLs [5,7,29]. This PTCL entity had the least abnormal genome [2], and is quite welldefined with unique clinical characteristics, pathological features and aberrant oncogenic pathways including the NF-κB pathway, IL-6 signaling, and the TGF-β pathway that have been identified to be enriched in AITL [30].…”

“…Actually, it was known that half of AITL have mutations in the TCR signaling pathways, including CD28 (13%), FYN (4.2%), PLCG1 (7.5%), STAT3 (3.1%), and VAV1 (4.3%) [31,43]. The majority of mutations in TCR genes were activating and acted as a driver of lymphomagenesis [5]. RHOA (G17V) mutations have been reported to activate TCR pathway through direct binding to VAV1, an essential mediator of TCR signaling, and increasing its phosphorylation [25].…”

Epigenetic targeting in lymphoma

“…78,83 These agents have shown particular promise in the field of T-cell lymphoma, in which recent molecular insights into underlying biology have prompted the exploration of demethylating agents and isocitrate dehydrogenase (IDH) inhibitors in angioimmunoblastic T-cell lymphoma (AITL) and related lymphomas. 88 In clinical trials of B-cell lymphoma treatment, the combination of epigenetic modifying agents with traditional immunochemotherapy or other novel agents remains a highly active area. 15 We begin our discussion with examples of epigenetic modification and techniques for characterising these abnormalities in lymphoma before reviewing the clinical data in this field, focussing on systemic rather than cutaneous lymphomas.…”