Differential expression and clinical significance of tyrosine-phosphorylated STAT3 in ALK+ and ALK- anaplastic large cell lymphoma.
OBJECTIVE
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.


METHODS
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 > or =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.
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002648:Child; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011485:Protein Binding; D050796:STAT3 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D016896:Treatment Outcome; D014443:Tyrosine / Q000378:metabolism*
D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014443:Tyrosine