1. JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma
- Author
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Young-Hyeh Ko, Leonard Tan, Tawatchai Pongpruttipan, Sucharita Dey, Jing Tan, Soon Thye Lim, Siok Bian Ng, S. T. Chin, Dachuan Huang, Kevin Tay, Jing Quan Lim, M. Tao, Choon Kiat Ong, Fen Zhang, Weng Khong Lim, Zhimei Li, Yan Hui Liu, Jeslin Chian Hung Ha, Tiffany Tang, Mohamad Farid, Steve Rozen, Maarja-Liisa Nairismagi, Vikneswari Rajasegaran, H. K. M. Koh, Gregory Poore, Lay Poh Khoo, Norimah A. Karim, K. L. Chuah, Puay Hoon Tan, W. L. Pang, Huilan Rao, Phaik-Leng Cheah, Sanjanaa Nagarajan, Y.-H. Ho, W. J. Chng, K. Sabai, Saranya Thangaraju, Giovani Claresta Wijaya, R. Quek, Soo Yong Tan, Yurike Laurensia, Cedric Chuan Young Ng, Bin Tean Teh, Shih-Sung Chuang, and Ioana Cutcutache
- 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 - 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.
- Published
- 2016