20 research outputs found
Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract.
Indolent T-cell lymphoproliferative disorders of the gastrointestinal tract are rare clonal T-cell diseases that more commonly occur in the intestines and have a protracted clinical course. Different immunophenotypic subsets have been described, but the molecular pathogenesis and cell of origin of these lymphocytic proliferations is poorly understood. Hence, we performed targeted next-generation sequencing and comprehensive immunophenotypic analysis of ten indolent T-cell lymphoproliferative disorders of the gastrointestinal tract, which comprised CD4 <sup>+</sup> (n=4), CD8 <sup>+</sup> (n=4), CD4 <sup>+</sup> /CD8 <sup>+</sup> (n=1) and CD4 <sup>-</sup> /CD8 <sup>-</sup> (n=1) cases. Genetic alterations, including recurrent mutations and novel rearrangements, were identified in 8/10 (80%) of these lymphoproliferative disorders. The CD4 <sup>+</sup> , CD4 <sup>+</sup> /CD8 <sup>+</sup> , and CD4 <sup>-</sup> /CD8 <sup>-</sup> cases harbored frequent alterations of JAK-STAT pathway genes (5/6, 82%); STAT3 mutations (n=3), SOCS1 deletion (n=1) and STAT3-JAK2 rearrangement (n=1), and 4/6 (67%) had concomitant mutations in epigenetic modifier genes (TET2, DNMT3A, KMT2D). Conversely, 2/4 (50%) of the CD8 <sup>+</sup> cases exhibited structural alterations involving the 3' untranslated region of the IL2 gene. Longitudinal genetic analysis revealed stable mutational profiles in 4/5 (80%) cases and acquisition of mutations in one case was a harbinger of disease transformation. The CD4 <sup>+</sup> and CD4 <sup>+</sup> /CD8 <sup>+</sup> lymphoproliferative disorders displayed heterogeneous Th1 (T-bet <sup>+</sup> ), Th2 (GATA3 <sup>+</sup> ) or hybrid Th1/Th2 (T-bet <sup>+</sup> /GATA3 <sup>+</sup> ) profiles, while the majority of CD8 <sup>+</sup> disorders and the CD4 <sup>-</sup> /CD8 <sup>-</sup> disease showed a type-2 polarized (GATA3 <sup>+</sup> ) effector T-cell (Tc2) phenotype. Additionally, CD103 expression was noted in 2/4 CD8 <sup>+</sup> cases. Our findings provide insights into the pathogenetic bases of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract and confirm the heterogeneous nature of these diseases. Detection of shared and distinct genetic alterations of the JAK-STAT pathway in certain immunophenotypic subsets warrants further mechanistic studies to determine whether therapeutic targeting of this signaling cascade is efficacious for a proportion of patients with these recalcitrant diseases
Composition of solid residue from thermal degradation of densely crosslinked polyorganosiloxanes
Impact on the chlorophyll concentration in the Bay of Bengal and Arabian Sea during Indian Ocean dipole mode
The effect of genotype and culture medium on somatic embryogenesis and plant regeneration from mature embryos of fourteen apomictic cultivars of buffel grass (Cenchrus ciliaris L.)
Effect of Implanted Helium on the Physicomechanical Properties of Armco Iron at the Temperatures of Manifestation of the Blue Brittleness Effect
Optimal designs with respect to Elfving's partial minimax criterion for heteroscedastic polynomial regression
Minimax criterion, heteroscedastic model, Chebyshev polynomial, 62K05,