JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphomaopen access
- Authors
- Nairismagi, ML[Nairismagi, M-L]; Tan, J[Tan, J.]; Lim, JQ[Lim, J. Q.]; Nagarajan, S[Nagarajan, S.]; Ng, CCY[Ng, C. C. Y.]; Rajasegaran, V[Rajasegaran, V.]; Huang, D[Huang, D.]; Lim, WK[Lim, W. K.]; Laurensia, Y[Laurensia, Y.]; Wijaya, GC[Wijaya, G. C.]; Li, ZM[Li, Z. M.]; Cutcutache, I[Cutcutache, I.]; Pang, WL[Pang, W. L.]; Thangaraju, S[Thangaraju, S.]; Ha, J[Ha, J.]; Khoo, LP[Khoo, L. P.]; Chin, ST[Chin, S. T.]; Dey, S[Dey, S.]; Poore, G[Poore, G.]; Tan, LHC[Tan, L. H. C.]; Koh, HKM[Koh, H. K. M.]; Sabai, K[Sabai, K.]; Rao, HL[Rao, H-L]; Chuah, KL[Chuah, K. L.]; Ho, YH[Ho, Y-H]; Ng, SB[Ng, S-B]; Chuang, SS[Chuang, S-S]; Zhang, F[Zhang, F.]; Liu, YH[Liu, Y-H]; Pongpruttipan, T[Pongpruttipan, T.]; Ko, YH[Ko, Y. H.]; Cheah, PL[Cheah, P-L]; Karim, N[Karim, N.]; Chng, WJ[Chng, W-J]; Tang, T[Tang, T.]; Tao, M[Tao, M.]; Tay, K[Tay, K.]; Farid, M[Farid, M.]; Quek, R[Quek, R.]; Rozen, SG[Rozen, S. G.]; Tan, P[Tan, P.]; Teh, BT[Teh, B. T.]; Lim, ST[Lim, S. T.]; Tan, SY[Tan, S-Y]; Ong, CK[Ong, C. K.]
- Issue Date
- Jun-2016
- Publisher
- NATURE PUBLISHING GROUP
- Citation
- LEUKEMIA, v.30, no.6, pp.1311 - 1319
- Indexed
- SCIE
SCOPUS
- Journal Title
- LEUKEMIA
- Volume
- 30
- Number
- 6
- Start Page
- 1311
- End Page
- 1319
- URI
- https://scholarworks.bwise.kr/skku/handle/2021.sw.skku/36451
- DOI
- 10.1038/leu.2016.13
- ISSN
- 0887-6924
- 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.
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Collections - Medicine > Department of Medicine > 1. Journal Articles
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