Recurrent presence of the PLCG1 S345F mutation in nodal peripheral T-cell lymphomas

Abstract

Peripheral T-cell lymphomas (PTCLs) are a group of nonHodgkin lymphomas (NHLs) with heterogeneous clinical presentation, histology, response to treatment and outcome, whose genetic background is still poorly understood. Patients with PTCL are usually treated with CHOP or more intensive regimens, generally with minimal effectiveness, thus highlighting the need for new therapeutic strategies.

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

“…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.…”

Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome

“…We detected recurrent PLCG1 gene variants in 11 patients including several variants reported previously [3][4][5][6][7][8][9]37 in MF and SS, as well as PTCL, AITL, and ATLL. 13,36 The PLCG1 S345F variant has been shown to induce expression of both NFAT via IP 3 activation and NF-kB via DAG activation of PKC signaling. This mutation is predicted to impair the auto-inhibitory function of PLCG1, which limits TCR signaling downstream of receptor ligation.…”

PLCG1 Gene Mutations Are Uncommon in Cutaneous T-Cell Lymphomas

“…Indeed, in the previous study, five out of the nine cases harboring the c.1034C4T/p.S345F were identified only with a sensitive allelespecific quantitative PCR assay (Vaque et al, 2014). On the other hand, our HRM/Sanger sequencing strategy identified two previously unknown PLCG1 mutations affecting the catalytic domain that would have been missed by the allele-specific mutation analysis used by our colleagues (Vaque et al, 2014;Manso et al, 2015).…”