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

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.

Keywords: Chronic lymphocytic leukemia; Epstein-Barr virus; latent membrane protein 1; signal transducer and activator of transcription 5.

Figure 1

Protein immunoblot results. The figure includes the immunoblot results of three subjects. One healthy blood donor expressing STAT5 but not STAT5b (none of the healthy subjects expressed STAT5b), one patient with CLL expressing STAT5 but not STAT5b, and one patient with CLL expressing both total STAT5 and STAT5b. STAT, signal transducer and activator of transcription; CCL, chronic lymphocytic leukemia.

Figure 2

Kaplan–Meier survival curves. (A) Survival by Stage (Binet Clinical Staging) 33; (B) EBV‐positive versus EBV‐negative patients; (C) LMP1‐positive versus LMP1‐negative patients; (D) STAT5‐positive versus STAT5‐negative patients; (E) STAT5b‐positive versus STAT5b‐negative patients; (F) Survival of patients based on the combined EBV and STAT5b status. EBV, Epstein–Barr virus; STAT; signal transducer and activator of transcription.