title: FACS analysis of Stat3/5 signaling reveals sensitivity to G-CSF and IL-6 as a significant prognostic factor in pediatric AML: a Children's Oncology Group report.
abstract: Signal transducer and activator of transcription 3 (Stat3) and Stat5 are critical signaling intermediates that promote survival in myeloid leukemias. We examined Stat3 and Stat5 activation patterns in resting and ligand-stimulated primary samples from pediatric patients with acute myeloid leukemia. Phosphorylated Stats were measured by FACS before and after stimulation with increasing doses of granulocyte-colony stimulating factor or IL-6. We also measured positive and negative regulators of Stat signaling, and we compared the variation in multiple parameters to identify biologic relationships. Levels of constitutively phosphorylated Stats were variable and did not correlate with survival. In terms of induced phospho-Stats, 15 of 139 specimens (11%) phosphorylated Stat3 in response to moderate doses of both granulocyte-colony stimulating factor and IL-6. Compared with groups that were resistant to 1 or both ligands, this pattern of dual sensitivity was associated with a superior outcome, with a 5-year event-free survival of 79% (P = .049) and 5-year overall survival of 100% (P = .006). This study provides important and novel insights into the biology of Stat3 and Stat5 signaling in acute myeloid leukemia. Patterns of ligand sensitivity may be valuable for improving risk identification, and for developing new agents for individualized therapy.
authors.affiliation: Division of Pediatric Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA. mlredell@txch.org
authors.forename: Michele S
authors.initials: MS
authors.lastname: Redell
authors.forename: Marcos J
authors.initials: MJ
authors.lastname: Ruiz
authors.forename: Robert B
authors.initials: RB
authors.lastname: Gerbing
authors.forename: Todd A
authors.initials: TA
authors.lastname: Alonzo
authors.forename: Beverly J
authors.initials: BJ
authors.lastname: Lange
authors.forename: David J
authors.initials: DJ
authors.lastname: Tweardy
authors.forename: Soheil
authors.initials: S
authors.lastname: Meshinchi
mesh_terms: D000293:Adolescent; D002469:Cell Separation; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D000069585:Filgrastim; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007223:Infant; D015850:Interleukin-6 / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation; D011379:Prognosis; D011994:Recombinant Proteins / Q000494:pharmacology; D012307:Risk Factors; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D055815:Young Adult
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D016179:Granulocyte Colony-Stimulating Factor; D000069585:Filgrastim