Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes

Abstract

Sézary Syndrome is a rare leukemic form of cutaneous T-cell lymphoma defined as erythroderma, adenopathy, and circulating atypical T-lymphocytes. It is rarely curable with poor prognosis. Here we present a multi-platform genomic analysis of 37 Sézary Syndrome patients that implicates dysregulation of the cell cycle checkpoint and T-cell signaling. Frequent somatic alterations were identified in TP53, CARD11, CCR4, PLCG1, CDKN2A, ARID1A, RPS6KA1, and ZEB1. Activating CCR4 and CARD11 mutations were detected in nearly a third of patients. ZEB1, a transcription repressor essential for T-cell differentiation, was deleted in over half of patients. IL32 and IL2RG were over-expressed in nearly all cases. Analysis of T-cell receptor Vβ and Vα expression revealed ongoing rearrangement of the receptors after the expansion of a malignant clone in one third of subjects. Our results demonstrate profound disruption of key signaling pathways in Sézary Syndrome and suggest potential targets for novel therapies.

Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell–derived lymphomas

“…Interestingly, some of the TCR-related genes may be altered through point mutations or small indels as well as by major structural rearrangements, amplifications, and deletions. 20,23,24 Collectively, these findings strongly suggest that genetic alterations affecting TCR signaling operate as a common pathogenic mechanism in several PTCL entities.…”

“…Ten different missense mutations spanning the coding region of PLCG1 (VF [2.1%; 38%]) were identified in 12 of 85 patients (8 AITL, 4 TFH-like PTCL; 14.1%) ( Figure 5A). Apart from previously reported variants in adult T-cell leukemia/lymphoma (ATLL) or in other PTCL, [20][21][22][23][24] we identified 2 novel variants (E730K and G869E). We generated all mutant constructs and tested their activity against WT PLCG1 in a FRET-based reporter assay of MALT1 protease activity 27,28 (Figure 5B) and in a NFAT luciferase reporter assay ( Figure 5C).…”

“…[20][21][22][23][24]53 Nonetheless, mutations in specific genes are variably recurrent in distinct entites, 24,25 and for a given gene, the distribution of the mutations and their relative prevalence are G869E E730K S520F S345F D1165G D1165H E1163K D342G R48W E47K PH1 PI heterogeneous. For instance, PLCG1 and CARD11 mutations are highly prevalent (up to 18% and 15% of the cases, respectively) in cutaneous T-cell lymphoma, in which conversely CD28 mutations are not found.…”

“…19 Mutations or gene fusions in costimulatory/TCR signaling genes as CD28, FYN, PLCG1, or CARD11 have also been reported in several PTCLs. 12,[20][21][22][23][24][25] However, alterations in the TCR signaling pathway have not yet been extensively studied in TFH-related lymphomas. Here, we focused on investigating mutations in the costimulatory/TCR signaling cascade in a series of AITL and TFHlike PTCLs using a targeted deep-sequencing approach.…”

Clinical impact of recurrently mutated genes on lymphoma diagnostics: state-of-the-art and beyond

“…52 Moreover, some gene mutations are mainly found in a specific lymphoma entity at a relatively high frequency, whereas they are rare in other subtypes, e.g. ID3 and TCF3 mutations in BL, 19 KLF2 in SMZL, [16][17][18] SF3B1 mutations in CLL, 14,15 RHOA mutations in AITL and other PTCL with a follicular helper T cell (T FH ) phenotype, 13,20,21,[53][54][55][56][57][58][59] and, very recently, the novel somatic mutations in RRAGC encoding a Rag GTPase protein (RagC) that were enriched in FL (16%) but were absent in other mature Bcell lymphomas. 60 That said, a pattern has started to emerge in recent years where certain lymphoma entities 'share' common types of genetic events affecting selected pathways or biological mechanisms ( Figure 1).…”