STAT3 mutation impacts biological and clinical features of T-LGL leukemia.

Antonella Teramo,Anna Cabrelle,Renato Zambello,Elisa Pagnin,Cédric Pastoret,Livio Trentin,Aline Moignet,Sara Teolato,Mikaël Roussel ,Monica Facco,Tamara Berno,Francesco Piazza,Elena De March,Matteo Leoncin,Cristina Gattazzo,Giulia Calabretto,Thierry Lamy,Elisa Boscaro,Gregorio Barilà,Chiara Ercolin,Gianpietro Semenzato

doi:10.18632/oncotarget.18711

Abstract

STAT3 mutations have been described in 30-40% of T-large granular lymphocyte (T-LGL) leukemia patients, leading to STAT3 pathway activation. Considering the heterogeneity of the disease and the several immunophenotypes that LGL clone may express, the aim of this work was to evaluate whether STAT3 mutations might be associated with a distinctive LGL immunophenotype and/or might be indicative for specific clinical features.Our series of cases included a pilot cohort of 101 T-LGL leukemia patients (68 CD8+/CD4- and 33 CD4+/CD8±) from Padua Hematology Unit (Italy) and a validation cohort of additional 20 patients from Rennes Hematology Unit (France).Our results indicate that i) CD8+ T-LGL leukemia patients with CD16+/CD56- immunophenotype identify a subset of patients characterized by the presence of STAT3 mutations and neutropenia, ii) CD4+/CD8± T-LGL leukemia are devoid of STAT3 mutations but characterized by STAT5b mutations, and iii) a correlation exists between STAT3 activation and presence of Fas ligand, this molecule resulting highly expressed in CD8+/CD16+/CD56- patients. Experiments with stimulation and inhibition of STAT3 phosphorylation confirmed this relationship. In conclusion, our data show that T-LGL leukemia with specific molecular and phenotypic patterns is associated with discrete clinical features contributing to get insights into molecular bases accounting for the development of Fas ligand-mediated neutropenia.

Highlights

T-cell large granular lymphocyte (T-LGL) leukemia is a rare chronic lymphoproliferative disorder characterized by the clonal expansion of CD3+ Large Granular Lymphocytes (LGL) [1,2,3]
Our results indicate that i) CD8+ T-LGL leukemia patients with CD16+/CD56immunophenotype identify a subset of patients characterized by the presence of STAT3 mutations and neutropenia, ii) CD4+/CD8± T-LGL leukemia are devoid of STAT3 mutations but characterized by STAT5b mutations, and iii) a correlation exists between STAT3 activation and presence of Fas ligand, this molecule resulting highly expressed in CD8+/CD16+/CD56- patients
In a large cohort of T-LGL leukemia patients we showed that the CD8+/CD16+/CD56- LGL phenotype correlates with a specific subset of T-LGL leukemia patients, characterized by STAT3 mutations and neutropenia

Summary

Introduction

T-cell large granular lymphocyte (T-LGL) leukemia is a rare chronic lymphoproliferative disorder characterized by the clonal expansion of CD3+ Large Granular Lymphocytes (LGL) [1,2,3]. Epling–Burnette et al [8] first demonstrated constitutive STAT3 activation with Mcl upregulation in T-LGL leukemia. We previously identified both extrinsic (IL-6 trans-signaling) and intrinsic mechanisms (SOCS3 downregulation) contributing to constitutive STAT3 tyrosine phosphorylation [9]. Somatic STAT3 and STAT5b mutations determining constitutive activation have been reported, the former detected in a proportion of approximately 40% of patients [10, 11] and the latter being associated to aggressive LGL disorders [12] and, as recently reported, to CD4+ T-LGL leukemia patients (6 out of 11 cases) [13]. High levels of circulating Fas ligand have been detected in T-LGL leukemia serum, likely triggering neutrophil apoptosis through the production of secreted Fas ligand [16]

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