STAT1 is phosphorylated and downregulated by the oncogenic tyrosine kinase NPM-ALK in ALK-positive anaplastic large-cell lymphoma. Blood 2015 Jul 16;126(3):336-45
Date
04/30/2015Pubmed ID
25921060DOI
10.1182/blood-2014-10-603738Scopus ID
2-s2.0-84937784820 (requires institutional sign-in at Scopus site) 24 CitationsAbstract
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.
Author List
Wu C, Molavi O, Zhang H, Gupta N, Alshareef A, Bone KM, Gopal K, Wu F, Lewis JT, Douglas DN, Kneteman NM, Lai RAuthor
Kathleen M. Bone PhD Associate Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
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
Mice
Mice, SCID
Phosphorylation
Proteasome Endopeptidase Complex
Protein-Tyrosine Kinases
RNA, Small Interfering
Receptor Protein-Tyrosine Kinases
STAT1 Transcription Factor
STAT3 Transcription Factor
Signal Transduction
Tumor Cells, Cultured
Ubiquitin
Xenograft Model Antitumor Assays