N-terminal truncation of STAT1 transcription factor causes CD3- and CD20-negative non-Hodgkin lymphoma through upregulation of STAT3-mediated oncogenic functions.

Publisher: BioMed Central Country of Publication: England NLM ID: 101170464 Publication Model: Electronic Cited Medium: Internet ISSN: 1478-811X (Electronic) Linking ISSN: 1478811X NLM ISO Abbreviation: Cell Commun Signal Subsets: MEDLINE

Original Publication: [London] : BioMed Central, c2003-

STAT1 Transcription Factor*/metabolism ; STAT1 Transcription Factor*/genetics ; STAT1 Transcription Factor*/chemistry ; STAT3 Transcription Factor*/metabolism ; Lymphoma, Non-Hodgkin*/metabolism ; Lymphoma, Non-Hodgkin*/pathology ; Lymphoma, Non-Hodgkin*/genetics ; Up-Regulation* ; Carcinogenesis*/pathology ; Carcinogenesis*/genetics; Animals ; Mice ; Phosphorylation ; Humans ; NF-kappa B/metabolism ; Cell Line, Tumor

Competing Interests: Declarations. Competing interests: The authors declare no competing interests.
The cytokine-driven transcription factor STAT1 (signal transducer and activator of transcription 1) executes anti-microbial and pro-apoptotic functions, and loss-of-function mutations are associated with increased susceptibility to various infections and the development of tumors. A targeted mutation in mice expressing an N-terminally truncated STAT1 protein (STAT1-ΔN) typically develops splenomegaly in animals older than 6 months due to the formation of splenic non-Hodgkin lymphomas. The expression of the STAT1-ΔN variant resulted in the disruption of normal spleen architecture by malignant CD3- and CD20-negative tumor cells, which stained positively for both tyrosine-phosphorylated STAT1 and STAT3. Immunoblotting of lysates from isolated tumor cells revealed the cytokine-independent hyperphosphorylation of both STAT proteins, whereas the expression level of NF-κB was significantly reduced. Gel-shift assays showed that the DNA-binding activity of STAT1-ΔN was increased compared to the wild-type protein. This elevated level of tyrosine-phosphorylated STAT1-ΔN did not further increase upon stimulation of isolated tumor cells with either interferon-γ (IFNγ), lipopolysaccharide (LPS), or the combination of both. Since the truncation mutant was unable to accumulate in the nucleus upon cytokine stimulation, real-time PCR data from tumor tissue as well as from isolated, IFNγ/LPS-treated lymphoma cells demonstrated significantly reduced STAT1-regulated target gene expression despite its observed hyperphosphorylation. The nuclear import defect of tyrosine-phosphorylated STAT1-ΔN was associated with an elevated tyrosine-phosphorylation level of its antagonistic homolog STAT3, which is a known oncogene. These data demonstrate that the lack of STAT1 nuclear accumulation interferes with the functional balance between the two STAT proteins and, thereby, promotes the formation of phospho-STAT3-expressing CD3 ^-/- CD20 ^-/- non-Hodgkin lymphomas in the spleens of the diseased animals.
(© 2025. The Author(s).)

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0 (STAT1 Transcription Factor)
0 (STAT3 Transcription Factor)
0 (NF-kappa B)

Date Created: 20250426 Date Completed: 20250427 Latest Revision: 20250429

20250429

PMC12034123

10.1186/s12964-025-02183-2

40287766