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Prognostic and therapeutic significance of phosphorylated STAT3 and protein tyrosine phosphatase-6 in peripheral-T cell lymphoma.

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.

SUBMITTER: Han JJ

PROVIDER: S-EPMC6232096 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Prognostic and therapeutic significance of phosphorylated STAT3 and protein tyrosine phosphatase-6 in peripheral-T cell lymphoma.

Han Jing Jing JJ O'byrne Megan M Stenson Mary J MJ Maurer Matthew J MJ Wellik Linda E LE Feldman Andrew L AL McPhail Ellen D ED Witzig Thomas E TE Gupta Mamta M

Blood cancer journal 20181112 11

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), respecti ...[more]

PMID: 30420593

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Project description:Background & Aims: Protein tyrosine phosphatase delta (PTPRD) is suppressed in several diseases including HCV infection. To identify hepatic pathways responsive to PTPRD function and their role in non-viral liver disease, we analyzed liver transcriptomic and clinical data from patients and established a Ptprd-deficient liver disease mouse model. Methods: Healthy patients were classified according to hepatic PTPRD expression and transcriptomic analysis was performed to identify signaling pathways associated with low PTPRD levels. We combined an animal model for metabolic dysfunction-associated steatohepatitis (MASH) with genetically impaired PTPRD expression (Ptprd+/-) to assess its impact on the liver transcriptome and metabolic function. Identified pathways were validated by perturbation studies in primary human hepatocytes and differentiated HepaRG cells. Substrate specificity was validated by pull-down assay. The clinical relevance was explored in a cohort of patients with fatty liver disease by ranking individuals according to hepatic PTPRD expression and analyzing its association with metabolic disease markers. Results: In healthy individuals and Ptprd+/- mice, PTPRD levels associated with hepatic glucose/lipid metabolism and peroxisomal function. Hepatic PTPRD expression is impaired in metabolic liver disease. Moreover, we revealed PTPRD as a STAT3 phosphatase in the liver, which is a regulator of peroxisomal function. Silencing of STAT3 in HepaRG cells treated with free-fatty acids was able to rescue the expression of genes implicated in lipid metabolism. During MASH, low hepatic PTPRD led to increased liver steatosis in the Ptprd+/- animals and pronounced unfolded protein response, which impacts insulin signaling. Silencing of PTPRD in PHH blunted insulin-induced AKT phosphorylation. In line with this, obese patients with low hepatic PTPRD expression exhibit increased levels of clinical markers associated with metabolic disease. Conclusion: Our data suggest an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis and how its impaired expression is associated with clinical manifestations of metabolic liver disease.

Dataset Information

Prognostic and therapeutic significance of phosphorylated STAT3 and protein tyrosine phosphatase-6 in peripheral-T cell lymphoma.

Publications

Prognostic and therapeutic significance of phosphorylated STAT3 and protein tyrosine phosphatase-6 in peripheral-T cell lymphoma.

Similar Datasets

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