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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
Haematologica September 2019 : haematol.2019.230961; doi:10.3324/haematol.2019.230961
Craig R. Soderquist
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA;
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Nupam Patel
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA;
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Vundavalli V. Murty
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA;
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Shane Betman
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA;
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Nidhi Aggarwal
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA;
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Ken H. Young
Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA;
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Luc Xerri
Department of Bio-Pathology, Institut Paoli-Calmettes, Aix-Marseille University, Marseille, France;
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Rebecca Leeman-Neill
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA;
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Suzanne K. Lewis
Department of Medicine, Celiac Disease Center, Columbia University Medical Center, New York, NY, USA;
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Peter H. Green
Department of Medicine, Celiac Disease Center, Columbia University Medical Center, New York, NY, USA;
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Susan Hsiao
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA;
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Mahesh M. Mansukhani
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA;
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Eric D. Hsi
Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA;
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Laurence de Leval
Institute of Pathology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
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Bachir Alobeid
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA;
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Govind Bhagat
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA;
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Author Affiliations

  1. Craig R. Soderquist1,*,
  2. Nupam Patel1,
  3. Vundavalli V. Murty1,
  4. Shane Betman1,
  5. Nidhi Aggarwal2,
  6. Ken H. Young3,
  7. Luc Xerri4,
  8. Rebecca Leeman-Neill1,
  9. Suzanne K. Lewis5,
  10. Peter H. Green5,
  11. Susan Hsiao1,
  12. Mahesh M. Mansukhani1,
  13. Eric D. Hsi6,
  14. Laurence de Leval7,
  15. Bachir Alobeid1 and
  16. Govind Bhagat1
  1. 1 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA;
  2. 2 Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA;
  3. 3 Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA;
  4. 4 Department of Bio-Pathology, Institut Paoli-Calmettes, Aix-Marseille University, Marseille, France;
  5. 5 Department of Medicine, Celiac Disease Center, Columbia University Medical Center, New York, NY, USA;
  6. 6 Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA;
  7. 7 Institute of Pathology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
  1. ↵* Corresponding author; email: crs2130{at}cumc.columbia.edu
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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.

  • Received July 8, 2019.
  • Accepted September 25, 2019.
  • Copyright © 2019, Ferrata Storti Foundation
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Keywords

Indolent Non-Hodgkin's Lymphoma
Lymphoproliferative Disorders
Cytogenetics and Molecular Genetics
immunophenotyping
Gastrointestinal Tract

Vol 104 Issue 12

Haematologica: 104 (12)
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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
Haematologica Sep 2019, haematol.2019.230961; DOI: 10.3324/haematol.2019.230961

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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
Haematologica Sep 2019, haematol.2019.230961; DOI: 10.3324/haematol.2019.230961
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