Expression of signal transducers and activators of transcription proteins in acute myeloid leukemia blasts.
Hematopoietic cytokine receptor signaling pathways involve activation of signal transducers and activators of transcription (STAT) proteins, which are postulated to be involved in cellular differentiation. Aberrant STAT isoforms (beta forms rather than the normal alpha forms) have been described and have been found to block the normal signaling pathway from the receptor. Bcr/Abl proteins have been suggested to directly activate STATs, without exposure to growth factors. We asked whether STATs play a role in leukemogenesis. We analyzed constitutive and induced patterns of STAT activity in pretreatment blasts from 36 newly diagnosed acute myeloid leukemia (AML) patients and studied protein tyrosine kinases (PTKs) that may be involved in STAT activity, using in vitro and in-gel kinase assays. The beta forms were expressed in 21 of 27 samples (78%). Constitutive STAT3 and STAT5 activity was found in samples from 28 and 22% of patients, respectively. Response to exogenous cytokines identified two groups. STAT activity in one group was modulated by exogenous cytokines: constitutive STAT activity increased in some patients but decreased or disappeared in response to cytokines in others. The second group was cytokine insensitive. Additionally, we found constitutive PTK activity in two patients whose blasts demonstrated constitutive STAT activity, suggesting that PTKs use cytokine receptor signal pathways to activate STATs in AML blasts without exposure to exogenous cytokines. Our data suggest that (a) constitutive expression of aberrant STATs may be involved in blocking differentiation of AML blasts, (b) exogenous cytokines may activate STAT-inhibitory pathways, and (c) STATs may be activated by PTKs in some AML blasts.
Department of Hematologic Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
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Xia
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Baer
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Block
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Baumann
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Wetzler
D000208:Acute Disease; D000328:Adult; D000368:Aged; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013926:Thrombopoietin / Q000494:pharmacology; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism*
D016207:Cytokines; D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013926:Thrombopoietin; D011505:Protein-Tyrosine Kinases