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JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma
- Source :
- Leukemia
- Publication Year :
- 2016
- Publisher :
- Nature Publishing Group, 2016.
-
Abstract
- Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.
- Subjects :
- 0301 basic medicine
Adult
Male
Cancer Research
Cell Survival
Biology
Deep sequencing
Receptors, G-Protein-Coupled
Loss of heterozygosity
03 medical and health sciences
Young Adult
0302 clinical medicine
Enteropathy-Associated T-Cell Lymphoma
Gene duplication
medicine
STAT5 Transcription Factor
Humans
Protein Kinase Inhibitors
Cells, Cultured
Aged
Janus Kinases
Aged, 80 and over
Gene Expression Profiling
JAK-STAT signaling pathway
Janus Kinase 3
Hematology
Amplicon
Middle Aged
medicine.disease
G Protein-Coupled Receptor Signaling
Gene expression profiling
STAT Transcription Factors
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Immunology
Mutation
Cancer research
Enteropathy-associated T-cell lymphoma
Original Article
Female
GTP-Binding Protein alpha Subunit, Gi2
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 14765551 and 08876924
- Volume :
- 30
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Leukemia
- Accession number :
- edsair.doi.dedup.....b8fe838eef7f10dfb9ef18e93ef53892