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.

Mutations in the JAK/STAT and RAS signaling pathways are common in intestinal T-cell lymphomas

“…Similar to the Nairismagi study, 6 we confirm the presence of a high incidence of JAK/STAT pathway mutations in EATL II (76% and 80%, respectively). In contrast to the 24% prevalence of GNAI2 mutations in that report, we did not identify any GNAI2 mutations in our 20 cases; rather we found a high percentage of RAS/RAF pathway mutations (31.6%), previously not reported in EATL II.…”

“…Until recently there were few genetic/genomic studies of these lymphomas, with the exceptions of a study of NK/T and γδ T-cell lymphomas that included cases of γδ EATL II 5 , and a second more comprehensive study of EATL II. 6 Both groups reported a high incidence of STAT5B mutations in EATL II, while the second group also identified frequent mutations of JAK3 and the α G-protein subunit GNAI2, as well as some less common mutations. To further understand the molecular pathogenesis of these rare lymphomas, we analyzed our own series of primary ITCL, which included EATL I, EATL II, and PTCL-NOS, by targeted next generation sequencing (NGS) of genes associated with T-cell neoplasia and proliferation.…”

“…These included genes previously reported to be mutated in T-cell lymphomas, components of the JAK/STAT pathway, and selected genes involved in T-cell receptor signaling and proliferation. Thirty-one and thirty-three samples, respectively, were also tested for mutations within JAK1 codon 1097, and GNAI2 codons 179 and 182 by targeted pyrosequencing, as these recently described mutational hotspots were not covered in the NGS panel 6, 8 . Further details of the pyrosequencing and NGS methods, and the list of genes analyzed are included in the supplemental methods and supplemental Table S2.…”

High incidence of activating STAT5B mutations in CD4-positive T-cell large granular lymphocyte leukemia

“…1 T-LGL leukemia have also been seen in various T-cell neoplasms, including gd hepatosplenic T-cell lymphoma, 13 T-cell acute lymphoblastic leukemia, 14,15 T-cell prolymphocytic leukemia, 16 type II enteropathy-associated T-cell lymphoma, 17 and extranodal NK/T-cell lymphoma, 18 suggesting that these are shared with other T-cell malignancies. The analyses of STAT5 target genes with chromatin immunoprecipitation sequencing have shown that STAT5B is a key factor in T-cell development, binding to molecules such as DOCK8, SNX9, FOXP3, and IL2RA.…”

Monomorphic epitheliotropic intestinal T‐cell lymphoma with T‐cell receptor (TCR) of silent phenotype shows rearrangement of TCRβ or TCRγ gene

“…MEITL is not associated with celiac disease (CD) that mainly occurs in Europe and it is distributed all over the world with predominance in Asia. Although it is well‐known that copy number gain of 9q34 is frequently found in MEITL in both of Asian and Western countries, the genetic alterations and mutational landscape of MEITL has been recently described, and MEITL is characterized by activating mutations of the JAK‐STAT pathway with mutations of STAT5B being the most common (reportedly as high as 63%) with other commonly mutated genes being JAK3 , GNAI2 , CREPBP and SETD2 . MEITL histologically shows a monomorphic proliferation of the lymphoma cells and immunohistochemically is positive for CD8, CD56 and megakaryocyte‐associated tyrosine kinase (MATK); the expression of TCRβ and TCRγ was variable among the cases.…”