Granulocyte colony-stimulating factor activation of Stat3 alpha and Stat3 beta in immature normal and leukemic human myeloid cells.
Granulocyte colony-stimulating factor (G-CSF) is the cytokine critical for directing neutrophilic granulocyte differentiation. Acute myelogenous leukemia (AML) cells, which frequently arise from this lineage, respond aberrantly to G-CSF by proliferating without differentiating. The basis for this abnormal responses is unknown. In the present study, we investigated whether G-CSF signaling in immature normal and leukemic human myeloid cells diverges at the level of activation of signal transducers and activators of transcription (STAT) proteins. We compared the profile of STAT proteins activated in G-CSF-stimulated immature normal and leukemic human myeloid cells. G-CSF activated Stat3 alpha in all AML cell lines examined except HL60 and in three of six uncultured AML patient samples. In normal human CD34+ bone marrow cells and HL60 cells, both reported to differentiate in response to G-CSF, G-CSF did not activate Stat3 alpha; rather, it activated only an 83 kD form of Stat3 that proved to be the human homologue of a short form of Stat3, Stat3 beta. Because the transcriptional activity of Stat3 beta is distinct from Stat3 alpha, these results suggest that the balance of the two Stat3 isoforms in myeloid cells may influence the cellular pattern of gene activation and consequently the ability of these cells to differentiate in response to G-CSF.
Chakraborty
A
A
Department of Medicine, University of Pittsburgh School of Medicine, PA, USA.
White
S M
SM
Schaefer
T S
TS
Ball
E D
ED
Dyer
K F
KF
Tweardy
D J
DJ
D000208:Acute Disease; D000595:Amino Acid Sequence; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D016179:Granulocyte Colony-Stimulating Factor