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Differential Expression and Clinical Significance of Tyrosine-phosphorylated STAT3 in ALK⁺ and ALK^- Anaplastic Large Cell Lymphoma

Department of Hematopathology, University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030 [J. D. K., L. J. M., G. Z. R., M. A. Y., P. T., V. L., M. H., H. M. A., R. L.], and Institute of Pathology, Albert-Ludwigs University of Freiburg, Freiburg, Germany [A. S-G., M. H.]

Purpose: Recent data suggest that nucleophosmin-anaplastic 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, pSTAT3^tyr705. In ALCL tumors, STAT3 was considered active when 20% of neoplastic cells show unequivocal nuclear immunostaining for pSTAT3^tyr705.

Results: All five ALK⁺ALCL cell lines showed strong pSTAT3^tyr705 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 5-year overall survival (P = 0.0076) but not failure-free 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.

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