Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract

Craig R. Soderquist; Nupam Patel; Vundavalli V. Murty; Shane Betman; Nidhi Aggarwal; Ken H. Young; Luc Xerri; Rebecca Leeman-Neill; Suzanne K. Lewis; Peter H. Green; Susan Hsiao; Mahesh M. Mansukhani; Eric D. Hsi; Laurence de Leval; Bachir Alobeid; Govind Bhagat

doi:10.3324/haematol.2019.230961

Author Affiliations

Craig R. Soderquist1,*,
Nupam Patel1,
Vundavalli V. Murty1,
Shane Betman1,
Nidhi Aggarwal2,
Ken H. Young3,
Luc Xerri4,
Rebecca Leeman-Neill1,
Suzanne K. Lewis5,
Peter H. Green5,
Susan Hsiao1,
Mahesh M. Mansukhani1,
Eric D. Hsi6,
Laurence de Leval7,
Bachir Alobeid1 and
Govind Bhagat1

¹ Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA;
² Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA;
³ Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA;
⁴ Department of Bio-Pathology, Institut Paoli-Calmettes, Aix-Marseille University, Marseille, France;
⁵ Department of Medicine, Celiac Disease Center, Columbia University Medical Center, New York, NY, USA;
⁶ Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA;
⁷ Institute of Pathology, Lausanne University Hospital (CHUV), Lausanne, Switzerland

↵* Corresponding author; email: crs2130{at}cumc.columbia.edu

Abstract

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 10 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%) lymphoproliferative disorders. The CD4+, CD4+/CD8+, and CD4-/CD8- cases harbored frequent alterations of the 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 were 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.