Prognostic significance of signal transducer and activator of transcription 5 and 5b expression in Epstein-Barr virus-positive patients with chronic lymphocytic leukemia.

Panagiotis T Diamantopoulos,Nefeli Giannakopoulou,Theodoros Vassilakopoulos,Zafiroula Georgoussi,Vasiliki Papadopoulou,Nikolaos Spanakis,Aglaia Dimitrakopoulou,Athanasios Galanopoulos,Fani Kalala,Elina Kontandreopoulou,Paschalina Pallaki,Maria Angelopoulou,Marie‐Christine Kyrtsonis,Maria Sofotasiou,Nora‐Athina Viniou,Panagiotis Zervakis

doi:10.1002/cam4.804

Abstract

Signal transducer and activator of transcription (STAT) proteins have been intensively studied in hematologic malignancies, and the efficacy of agents against STATs in lymphomas is already under research. We investigated the expression of total STAT5 and STAT5b in peripheral blood samples of patients with chronic lymphocytic leukemia (CLL) in correlation with the presence of Epstein–Barr Virus (EBV) and its major oncoprotein (latent membrane protein 1, LMP1). The EBV load was measured in the peripheral blood by real‐time PCR for the BXLF1 gene and the levels of LMP1 by PCR and ELISA. Western blotting was performed for total STAT5 and STAT5b in protein extracts. STAT5b was only expressed in patients (not in healthy subjects) and STAT5 but particularly STAT5b expression was correlated with the presence of the virus (77.3% vs. 51.2%, P = 0.006 for STAT5b) and to the expression of LMP1 (58.3% vs. 21.6%, P = 0.011 for STAT5b). Moreover, the expression of STAT5b and the presence of EBV and LMP1 were strongly negatively correlated with the overall survival of the patients (log‐rank test P = 0.011, 0.015, 0.006, respectively). Double positive (for EBV and STAT5b) patients had the lowest overall survival (log‐rank test P = 0.013). This is the first report of a survival disadvantage of EBV+ patients with CLL, and the first time that STAT5b expression is correlated with survival. The correlation of STAT5 expression with the presence of the virus, along with our survival correlations defines a subgroup of patients with CLL that may benefit from anti‐STAT agents.

Highlights

The signal transducer and activator of transcription (STAT) proteins are cytosolic transcription factors that, upon activation by extracellular cytokines through receptor- associated tyrosine kinases, dimerize and migrate to the nucleus to control gene expression
chronic lymphocytic leukemia (CLL) does not belong to the Epstein–Barr Virus (EBV)-r elated lymphoproliferative disorders, but there are several studies implying that EBV may play a role in the pathogenesis, course and prognosis of the disease
Preliminary reports had proposed that CLL B cells are rather resistant to the transforming actions of the virus [36], LMP1 has been previously detected in B cells from patients with CLL [28, 29, 37], but the role of the virus in the pathogenesis of the disease has not yet been clarified, its presence has been related to a more aggressive course and to Richter’s transformation [38,39,40]

Summary

Introduction

The signal transducer and activator of transcription (STAT) proteins are cytosolic transcription factors that, upon activation by extracellular cytokines through receptor- associated tyrosine kinases, dimerize and migrate to the nucleus to control gene expression. Inhibition of STAT3 and STAT5 signaling has been shown to arrest the growth of several cancer models [3], and cancer cells are more dependent. Expression of STAT5 and STAT5b in EBV-Positive Patients with CLL on STAT activity than normal cells [4]. These two features render the STAT family a potential therapeutic target for malignancies, where potent growth inhibition could be coupled with limited toxicity. STAT inhibitors have been used in vitro and in animal models to suppress the proliferation of lymphoma cells, and antisense oligonucleotide drugs against STAT proteins have been used in phase 1 and 2 clinical trials against lymphomas with promising results [5]

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Conclusion