TY - JOUR AU - Craig R. Soderquist, AU - Nupam Patel, AU - Vundavalli V. Murty, AU - Shane Betman, AU - Nidhi Aggarwal, AU - Ken H. Young, AU - Luc Xerri, AU - Rebecca Leeman-Neill, AU - Suzanne K. Lewis, AU - Peter H. Green, AU - Susan Hsiao, AU - Mahesh M. Mansukhani, AU - Eric D. Hsi, AU - Laurence de Leval, AU - Bachir Alobeid, AU - Govind Bhagat, PY - 2020/07/01 Y2 - 2024/03/29 TI - Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract JF - Haematologica JA - haematol VL - 105 IS - 7 SE - Articles DO - 10.3324/haematol.2019.230961 UR - https://haematologica.org/article/view/9941 SP - 1895-1906 AB - 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+ (n=4), CD8+ (n=4), CD4+/CD8+ (n=1) and CD4−/CD8− (n=1) cases. Genetic alterations, including recurrent mutations and novel rearrangements, were identified in 8/10 (80%) of these lymphoproliferative disorders. The CD4+, CD4+/CD8+, and CD4−/CD8− 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+ 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+ and CD4+/CD8+ lymphoproliferative disorders displayed heterogeneous Th1 (T-bet+), Th2 (GATA3+) or hybrid Th1/Th2 (T-bet+/GATA3+) profiles, while the majority of CD8+ disorders and the CD4−/CD8− disease showed a type-2 polarized (GATA3+) effector T-cell (Tc2) phenotype. Additionally, CD103 expression was noted in 2/4 CD8+ 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. ER -