STAT1 is phosphorylated and downregulated by the oncogenic tyrosine kinase NPM-ALK in ALK-positive anaplastic large-cell lymphoma.
The tumorigenicity of most cases of ALK-positive anaplastic large-cell lymphoma (ALK+ ALCL) is driven by the oncogenic fusion protein NPM-ALK in a STAT3-dependent manner. Because it has been shown that STAT3 can be inhibited by STAT1 in some experimental models, we hypothesized that the STAT1 signaling pathway is defective in ALK+ ALCL, thereby leaving the STAT3 signaling unchecked. Compared with normal T cells, ALK+ ALCL tumors consistently expressed a low level of STAT1. Inhibition of the ubiquitin-proteasome pathway appreciably increased STAT1 expression in ALK+ ALCL cells. Furthermore, we found evidence that NPM-ALK binds to and phosphorylates STAT1, thereby promoting its proteasomal degradation in a STAT3-dependent manner. If restored, STAT1 is functionally intact in ALK+ ALCL cells, because it effectively upregulated interferon-γ, induced apoptosis/cell-cycle arrest, potentiated the inhibitory effects of doxorubicin, and suppressed tumor growth in vivo. STAT1 interfered with the STAT3 signaling by decreasing STAT3 transcriptional activity/DNA binding and its homodimerization. The importance of the STAT1/STAT3 functional interaction was further highlighted by the observation that short interfering RNA knockdown of STAT1 significantly decreased apoptosis induced by STAT3 inhibition. Thus, STAT1 is a tumor suppressor in ALK+ ALCL. Phosphorylation and downregulation of STAT1 by NPM-ALK represent other mechanisms by which this oncogenic tyrosine kinase promotes tumorigenesis.
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada;
Chengsheng
C
Wu
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada; Faculty of Pharmacy, Tabriz University of Medical Science, Tabriz, East Azerbaijan Province, Iran;
Ommoleila
O
Molavi
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada; Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China;
Haifeng
H
Zhang
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada;
Nidhi
N
Gupta
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada;
Abdulraheem
A
Alshareef
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada;
Kathleen M
KM
Bone
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada;
Keshav
K
Gopal
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada;
Fang
F
Wu
Department of Surgery and.
Jamie T
JT
Lewis
Department of Surgery and.
Donna N
DN
Douglas
Department of Surgery and.
Norman M
NM
Kneteman
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada; and DynaLIFE Dx Medical Laboratories, Edmonton, AB, Canada.
Raymond
R
Lai
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; D025801:Ubiquitin; D007371:Interferon-gamma; C107023:p80(NPM-ALK) protein; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D046988:Proteasome Endopeptidase Complex