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Leukemia. 2016 Jun;30(6):1311-9. doi: 10.1038/leu.2016.13. Epub 2016 Feb 8.

JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma.

Author information

1
Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
2
Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.
3
Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
4
Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore.
5
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
6
Department of Biomedical Engineering, Duke University, Durham, NC, USA.
7
Department of Pathology, Singapore General Hospital, Singapore, Singapore.
8
Advanced Molecular Pathology Laboratory, Singapore Health Services, Singapore, Singapore.
9
Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
10
Department of Pathology, Tan Tock Seng Hospital, Singapore, Singapore.
11
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
12
Department of Pathology, National University Hospital, National University Health System, Singapore, Singapore.
13
Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan.
14
Department of Pathology, Taipei Medical University and National Taiwan University, Taipei, Taiwan.
15
Department of Pathology, Guangdong General Hospital, Guangzhou, China.
16
Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
17
Department of Pathology, Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, South Korea.
18
Department of Pathology, University of Malaya, Kuala Lumpur, Malaysia.
19
Department of Pathology, Hospital Raja Permaisuri Bainun, Ipoh, Malaysia.
20
Department of Haematology-Oncology, National University Hospital, National University Health System, Singapore, Singapore.
21
Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
22
Genome Institute of Singapore, A*STAR, Singapore, Singapore.
23
Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore.
24
Office of Education, Duke-NUS Medical School, Singapore, Singapore.

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.

PMID:
26854024
PMCID:
PMC4895162
DOI:
10.1038/leu.2016.13
[Indexed for MEDLINE]
Free PMC Article

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