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

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.

• Authors: M-L Nairismägi, J Tan, J Q Lim, S Nagarajan, C C Y Ng, V Rajasegaran, D Huang, W K Lim, Y Laurensia, G C Wijaya, Z M Li, I Cutcutache, W L Pang, S Thangaraju, J Ha, L P Khoo, S T Chin, S Dey, G Poore, L H C Tan, H K M Koh, K Sabai, H-L Rao, K L Chuah, Y-H Ho, S-B Ng, S-S Chuang, F Zhang, Y-H Liu, T Pongpruttipan, Y H Ko, P-L Cheah, N Karim, W-J Chng, T Tang, M Tao, K Tay, M Farid, R Quek, S G Rozen, P Tan, B T Teh, S T Lim, S-Y Tan, C K Ong
• Journal: Leukemia (Leukemia) Vol. 30 Issue 6 Pg. 1311-9 (06 2016) ISSN: 1476-5551 [Electronic] England
• PMID: 26854024 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Receptors, G-Protein-Coupled
• STAT Transcription Factors
• STAT5 Transcription Factor
• STAT5B protein, human
• Janus Kinase 3
• Janus Kinases
• GNAI2 protein, human
• GTP-Binding Protein alpha Subunit, Gi2

Topics

• Adult
• Aged
• Aged, 80 and over
• Cell Survival (drug effects)
• Cells, Cultured
• Enteropathy-Associated T-Cell Lymphoma (metabolism, pathology)
• Female
• GTP-Binding Protein alpha Subunit, Gi2 (genetics)
• Gene Expression Profiling
• Humans
• Janus Kinase 3 (genetics)
• Janus Kinases (metabolism)
• Male
• Middle Aged
• Mutation
• Protein Kinase Inhibitors (pharmacology)
• Receptors, G-Protein-Coupled (metabolism)
• STAT Transcription Factors (metabolism)
• STAT5 Transcription Factor (genetics)
• Signal Transduction (drug effects)
• Young Adult