Investigating the Role of Common Gamma Chain Signaling in Peripheral T-Cell Lymphoma

Abstract

Peripheral T-cell lymphoma (PTCL) is a rare aggressive Non-Hodgkin's lymphoma with extremely poor prognosis and inadequate response to current therapies. The molecular mechanisms driving PTCL oncogenesis are incompletely understood. Identification of cancer driver mutations is therefore needed to facilitate the development of improved targeted therapeutic approaches. Recent sequencing studies have reported mutations in genes involved in many signaling pathways in PTCL including DNA repair, epigenetic regulation, and T-cell receptor signal transduction. Notably, activating mutations in the common gamma chain (γc)/JAK/STAT signaling pathway are especially prevalent in PTCL. In this study, we identify oncogenic driver mutations and assess the JAK/STAT signaling pathway as a therapeutic target in PTCL. We report the results of a whole-exome sequencing analysis of 12 PTCL patient samples identifying recurrent somatic missense/nonsense mutations in ATM (Ataxia-Telangiectasia Mutated) in four samples and the γc signaling pathway (JAK3, γc, STAT5B) in three samples, all of which also harbored mutations in ATM. We next aimed to determine if the previously uncharacterized γc mutation we identified, K315E, serves as an oncogenic driver in PTCL. Our results suggest that K315E mutation does not independently induce constitutive JAK/STAT pathway activation in PTCL. Inhibition of STAT5, a downstream transcription factor of the JAK/STAT pathway, is an appealing therapeutic strategy as it has been reported to be frequently mutated and aberrantly activated in PTCL, and is associated with worse clinical outcomes. Therefore, we assessed the effect of STAT5 inhibition in PTCL. We determined that the drug pimozide, a STAT5 inhibitor, induces cell death via the extrinsic apoptotic pathway in PTCL involving TRAIL/DR4 signaling. Pimozide also induces apoptosis in primary PTCL cells ex vivo. We further report a novel synergistic drug combination of pimozide with the PARP inhibitor olaparib to target ATM deficient PTCL cells, based on the frequency of concurrent ATM mutations and JAK/STAT pathway mutations demonstrated in PTCL. Taken together, these data enhance our understanding of the role of γc signaling in PTCL and support targeting this pathway in the treatment of this aggressive malignancy.