title: Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival.
abstract: Signal transducer and activator of transcription (STAT) proteins are involved in hematopoietic cytokine receptor signaling pathways that regulate cell proliferation, differentiation, and survival. STATs are dysregulated in acute myeloid leukemia (AML); mechanisms of dysregulation include constitutive activation and truncation of the C-terminal transactivation domain; the latter results in a beta isoform that has a trans-dominant negative effect on gene induction mediated by the full-length STAT alpha form. It was hypothesized that constitutive STAT activity might correlate with unfavorable treatment outcome in AML. Pretreatment bone marrow samples from 63 adult patients with AML were analyzed by electrophoretic mobility shift assay for the presence of STAT DNA-binding activity. Isoforms and relative levels of STAT proteins were determined by immunoblotting. Constitutive STAT3 activity was detected in samples from 28 (44%) patients. Pretreatment clinical characteristics, expression of STAT alpha/beta isoforms, and treatment regimens did not differ significantly between patients with and without constitutive STAT3 activity. Disease-free survival (DFS) was significantly shorter in patients with than in patients without constitutive STAT3 activity (median 8.7 vs 20.6 months; P =.01). Overall survival did not differ significantly. The subgroup of patients with constitutive STAT3 activity and the STAT3 beta isoform had the shortest DFS (P =.006) and shorter overall survival (P =.049) than all other patients. Whether adverse treatment outcome is attributable to constitutive STAT activity itself or to a process that leads to constitutive STAT activity remains to be determined. This is the first demonstration of a prognostic significance for STAT proteins in a malignancy.
authors.affiliation: Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Benekli
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xia
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Donohue
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Ford
authors.forename: Lynda A
authors.initials: LA
authors.lastname: Pixley
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
authors.forename: Heinz
authors.initials: H
authors.lastname: Baumann
authors.forename: Meir
authors.initials: M
authors.lastname: Wetzler
mesh_terms: D001853:Bone Marrow / Q000737:chemistry; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000502:physiology*; D018572:Disease-Free Survival; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D020033:Protein Isoforms / Q000032:analysis; D012074:Remission Induction; D050796:STAT3 Transcription Factor; D015996:Survival Rate; D015534:Trans-Activators / Q000032:analysis / Q000502:physiology*; D016896:Treatment Outcome
chemical_list: D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D004247:DNA