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| Status |
Public on Oct 22, 2020 |
| Title |
Genome-wide transcriptome analysis of the STAT6-regulated genes in advanced-stage cutaneous T-cell lymphoma [Bulk-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by genome tiling array
|
| Summary |
The signal transducer and activator of transcription 6 (STAT-6) is a critical up-stream mediator of IL-13 and IL-4 signaling and is constitutively activated in malignant lymphocytes from Sezary syndrome (SS) and mycosis fungoides (MF), the most common subtypes of cutaneous T-cell lymphomas. By combining genome-wide expression profiling with pharmacological STAT-6 inhibition, we have identified the genes regulated by STAT-6 in MF/SS tumors. We found that STAT-6 regulates several common pathways in MF/SS malignant lymphocytes that are associated with control of cell cycle progression and genomic stability as well as production of Th2 cytokines. Using ex vivo skin explants from cutaneous MF tumors as well as Sezary cells derived from the blood of SS patients, we demonstrated that inhibition of STAT-6 activation down-regulates cytokine production and induces cell cycle arrest in MF/SS malignant lymphocytes, inhibiting their proliferation but not their survival. Furthermore, we show that STAT-6 promotes the pro-tumoral M2-like phenotype of tumor-associated macrophages in the tumor microenvironment of advanced-stage MF by up-regulating the expression of genes associated with immunosuppression, chemotaxis, and tumor matrix remodeling. Thus, we show STAT-6 to be a major factor in the pathogenesis and progression of MF/SS, promoting proliferation and invasion of the malignant lymphocytes while inducing a progressive depression of the anti-tumor immune response. Together, our results provide new insights into disease pathogenesis and offer new prospective targets for therapeutic intervention.
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| Overall design |
3 MF samples, 4 SZ samples and 3 normal control samples were cultured for 48 hours with or without the STAT6 inhibitor and then analyzed with RNAseq.
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| Contributor(s) |
Gaydosik AM, Queen DS, Akilov OE, Geskin LJ, Fuschiotti P |
| Citation(s) |
32438399 |
| |
| Submission date |
Apr 01, 2020 |
| Last update date |
Oct 22, 2020 |
| Contact name |
Patrizia Fuschiotti |
| E-mail(s) |
paf23@pitt.edu
|
| Organization name |
University of Pittsburgh
|
| Street address |
200 Lothrop St
|
| City |
Pittsburgh |
| State/province |
PA |
| ZIP/Postal code |
15261 |
| Country |
USA |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (20)
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| This SubSeries is part of SuperSeries: |
| GSE147947 |
Genome-wide transcriptome analysis of the STAT6-regulated genes in advanced-stage cutaneous T-cell lymphoma |
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| Relations |
| BioProject |
PRJNA622529 |
| SRA |
SRP254913 |
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