Differential Expression and Clinical Significance of Tyrosinephosphorylated STAT3 in ALK⁺ and ALK⁻ Anaplastic Large Cell Lymphoma

Purpose: Recent data suggest that nucleophosminanaplastic lymphoma kinase (NPM-ALK) activates signal transducers and activators of transcription 3 (STAT3) directly, and ALK expression correlates with STAT3 activation in non-Hodgkin's lymphomas. In this study, we evaluated comprehensively STAT3 activation status in anaplastic large cell lymphoma (ALCL) cell lines and pretreatment ALCL tumors. Experimental Design: The study included five ALK⁺ ALCL cell lines and 80 systemic ALCL tumors (31 ALK⁺, 49 ALK⁻) that were formalin fixed and paraffin embedded. All 80 patients with systemic ALCL were treated with doxorubicin-based chemotherapy. The STAT3 activation status in cell lines was determined using Western blots and an antibody that reacts specifically with the phosphorylated tyrosine 705 of STAT3, pSTAT^3tyr705. In ALCL tumors, STAT3 was considered active when ≥20% of neoplastic cells show unequivocal nuclear immunostaining for pSTAT^3tyr705. Results: All five ALK⁺ALCL cell lines showed strong pSTAT3tyr705 expression on Western blots. In systemic ALCL, STAT3 activation was detected in 49 of 80 (61%) ALCL tumors: 26 of 31 (84%) ALK⁺ tumors and 23 of 49 (47%) ALK⁻ tumors. ALK expression correlated significantly with STAT3 activation (P < 0.0001). Clinical follow-up data were available for 72 patients. In the ALK⁻ group, the lack of STAT3 activation correlated with a favorable favorable 5-year overall survival (P = 0.0076) but not failurefree survival. In the ALK⁺ group, patients with inactive STAT3 showed a trend toward longer overall survival (P = 0.09) and failure-free survival (P = 0.19). Importantly, all five ALK⁺ ALCL patients with inactive STAT3 survived without treatment failure after a median follow-up of 83 months. Conclusions: STAT3 activation correlates with but is not strictly dependent on ALK expression in ALCL. Lack of STAT3 activation appears to correlate with a favorable clinical outcome in ALCL.