Please use this identifier to cite or link to this item: https://doi.org/10.1038/leu.2016.13
Title: JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma
Authors: Nairismagi, M-L
Tan, J
Lim, JQ
Nagarajan, S 
Ng, CCY
Rajasegaran, V
Huang, D
Lim, WK
Laurensia, Y
Wijaya, GC 
Li, ZM
Cutcutache, I 
Pang, WL
Thangaraju, S 
Ha, J
Khoo, LP
Chin, ST
Dey, S
Poore, G
Tan, LHC 
Koh, HKM
Sabai, K
Rao, H-L
Chuah, KL
Ho, Y-H
Ng, S-B 
Chuang, S-S
Zhang, F
Liu, Y-H
Pongpruttipan, T
Ko, YH
Cheah, P-L
Karim, N
Chng, W-J
Tang, T
Tao, M
Tay, K
Farid, M
Quek, R
Rozen, SG
Tan, P
Teh, BT
Lim, ST
Tan, S-Y
Ong, CK
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
Hematology
GAMMA-DELTA-T
INTEGRATIVE GENOMICS VIEWER
FOLLICULAR LYMPHOMA
ALPHA-SUBUNIT
MAP KINASE
MUTATIONS
CANCER
GENES
EXPRESSION
POPULATION
Issue Date: 1-Jun-2016
Publisher: NATURE PUBLISHING GROUP
Citation: Nairismagi, M-L, Tan, J, Lim, JQ, Nagarajan, S, Ng, CCY, Rajasegaran, V, Huang, D, Lim, WK, Laurensia, Y, Wijaya, GC, Li, ZM, Cutcutache, I, Pang, WL, Thangaraju, S, Ha, J, Khoo, LP, Chin, ST, Dey, S, Poore, G, Tan, LHC, Koh, HKM, Sabai, K, Rao, H-L, Chuah, KL, Ho, Y-H, Ng, S-B, Chuang, S-S, Zhang, F, Liu, Y-H, Pongpruttipan, T, Ko, YH, Cheah, P-L, Karim, N, Chng, W-J, Tang, T, Tao, M, Tay, K, Farid, M, Quek, R, Rozen, SG, Tan, P, Teh, BT, Lim, ST, Tan, S-Y, Ong, CK (2016-06-01). JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma. LEUKEMIA 30 (6) : 1311-1319. ScholarBank@NUS Repository. https://doi.org/10.1038/leu.2016.13
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 .
Source Title: LEUKEMIA
URI: https://scholarbank.nus.edu.sg/handle/10635/206601
ISSN: 08876924
14765551
DOI: 10.1038/leu.2016.13
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