Oncotarget

Research Papers:

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

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

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Oncotarget. 2017; 8:61876-61889. https://doi.org/10.18632/oncotarget.18711

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Abstract

Antonella Teramo1,2,*, Gregorio Barilà1,2,*, Giulia Calabretto1,2, Chiara Ercolin1,2, Thierry Lamy3, Aline Moignet3, Mikael Roussel4, Cédric Pastoret4, Matteo Leoncin1, Cristina Gattazzo1,2, Anna Cabrelle2, Elisa Boscaro1, Sara Teolato1, Elisa Pagnin1, Tamara Berno1, Elena De March1, Monica Facco1,2, Francesco Piazza1,2, Livio Trentin1,2, Gianpietro Semenzato1,2 and Renato Zambello1,2

1Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy

2Venetian Institute of Molecular Medicine (VIMM), Padua, Italy

3Department of Clinical Hematology, University Hospital of Rennes, Rennes, France

4Biology Department, University Hospital of Rennes, Rennes, France

*These authors have contributed equally to this work

Correspondence to:

Renato Zambello, email: r.zambello@unipd.it

Keywords: large granular lymphocyte leukemia, STAT3 mutation, immunophenotype, neutropenia, fas ligand

Received: January 20, 2017    Accepted: May 22, 2017    Published: June 27, 2017

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.


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