STAT1 is phosphorylated and downregulated by the oncogenic tyrosine kinase NPM-ALK in ALK-positive anaplastic large-cell lymphoma.

Abstract

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.

• Authors: Chengsheng Wu, Ommoleila Molavi, Haifeng Zhang, Nidhi Gupta, Abdulraheem Alshareef, Kathleen M Bone, Keshav Gopal, Fang Wu, Jamie T Lewis, Donna N Douglas, Norman M Kneteman, Raymond Lai
• Journal: Blood (Blood) Vol. 126 Issue 3 Pg. 336-45 (Jul 16 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 25921060 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

• RNA, Small Interfering
• STAT1 Transcription Factor
• STAT1 protein, human
• STAT3 Transcription Factor
• Ubiquitin
• Interferon-gamma
• p80(NPM-ALK) protein
• ALK protein, human
• Alk protein, mouse
• Anaplastic Lymphoma Kinase
• Protein-Tyrosine Kinases
• Receptor Protein-Tyrosine Kinases
• Proteasome Endopeptidase Complex

Topics

• Anaplastic Lymphoma Kinase
• Animals
• Apoptosis
• Blotting, Western
• Case-Control Studies
• Cell Proliferation
• Cell Transformation, Neoplastic
• Down-Regulation
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Immunoenzyme Techniques
• Interferon-gamma
• Lymphoma, Large-Cell, Anaplastic (genetics, metabolism, pathology)
• Mice
• Mice, SCID
• Phosphorylation
• Proteasome Endopeptidase Complex (metabolism)
• Protein-Tyrosine Kinases (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Receptor Protein-Tyrosine Kinases (metabolism)
• STAT1 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Tumor Cells, Cultured
• Ubiquitin (metabolism)
• Xenograft Model Antitumor Assays