Abstract
Peripheral T cell lymphomas (PTCL) is a heterogenous group of non-Hodgkin lymphoma and many patients remain refractory to the frontline therapy. Identifying new prognostic markers and treatment is an unmet need in PTCL. We analyzed phospho-STAT3 (pSTAT3) expression in a cohort of 169 PTCL tumors and show overall 38% positivity with varied distribution among PTCL subtypes with 27% (16/59) in PTCL-NOS; 29% (11/38) in AITL, 57% (13/28) in ALK-negative ALCL, and 93% in ALK-pos ALCL (14/15), respectively. Correlative analysis indicated an adverse correlation between pSTAT3 and overall survival (OS). PTPN6, a tyrosine phosphatase and potential negative regulator of STAT3 activity, was suppressed in 62% of PTCL-NOS, 42% of AITL, 60% ALK-neg ALCL, and 86% of ALK-pos ALCL. Loss of PTPN6 combined with pSTAT3 positivity predicted an infwere considered significantferior OS in PTCL cases. In vitro treatment of TCL lines with azacytidine (aza), a DNA methyltransferase inhibitor (DNMTi), restored PTPN6 expression and decreased pSTAT3. Combining DNMTi with JAK3 inhibitor resulted in synergistic antitumor activity in SUDHL1 cell line. Overall, our results suggest that PTPN6 and activated STAT3 can be developed as prognostic markers, and the combination of DNMTi and JAK3 inhibitors as a novel treatment for patients with PTCL subtypes.
Highlights
Introduction PeripheralT cell lymphomas (PTCL) represent approximately 10% of all lymphomas in the United States[1]
These results suggest that pSTAT3 is differentially expressed among Peripheral T cell lymphomas (PTCL) subtypes
While pSTAT3 expression was robust in all three anaplastic large cell (ALCL) cell lines (Karpas[299], SUDHL1, and SR786), only moderate pSTAT3 signal was detected in Mycosis fungoides (MF) origin cutaneous TCL (CTCL) lines (MyLa); CTCL lines of Sezary syndrome (SS) origin (Hut-78 and SeAX) like normal CD3+ T cells lacked pSTAT3 expression
Summary
Introduction PeripheralT cell lymphomas (PTCL) represent approximately 10% of all lymphomas in the United States[1]. PTCL is a heterogeneous disease and has been categorized by the World Health Organization into several subtypes including peripheral TCL-not otherwise specified (PTCL-NOS), angioimmunoblastic TCL (AITL), anaplastic large cell (ALCL), and the predominant subsets of cutaneous TCL (CTCL)[2]. Because of this broad morphological spectrum and immunophenotypic variations among patients, the pathogenesis of PTCLs remains poorly understood.
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