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

Optimal designs with respect to Elfving's partial minimax criterion for heteroscedastic polynomial regression

Minimax criterion, heteroscedastic model, Chebyshev polynomial, 62K05,