GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features

Blood. 2014 May 8;123(19):3007-15. doi: 10.1182/blood-2013-12-544809. Epub 2014 Feb 4.

Abstract

The cell of origin and the tumor microenvironment's role remain elusive for the most common peripheral T-cell lymphomas (PTCLs). As macrophages promote the growth and survival of malignant T cells and are abundant constituents of the tumor microenvironment, their functional polarization was examined in T-cell lymphoproliferative disorders. Cytokines that are abundant within the tumor microenvironment, particularly interleukin (IL)-10, were observed to promote alternative macrophage polarization. Macrophage polarization was signal transducer and activator of transcription 3 dependent and was impaired by the Janus kinase inhibitor ruxolitinib. In conventional T cells, the production of T helper (Th)2-associated cytokines and IL-10, both of which promote alternative macrophage polarization, is regulated by the T-cell transcription factor GATA-binding protein 3 (GATA-3). Therefore, its role in the T-cell lymphomas was examined. GATA-3 expression was observed in 45% of PTCLs, not otherwise specified (PTCL, NOS) and was associated with distinct molecular features, including the production of Th2-associated cytokines. In addition, GATA-3 expression identified a subset of PTCL, NOS with distinct clinical features, including inferior progression-free and overall survival. Collectively, these data suggest that further understanding the cell of origin and lymphocyte ontogeny among the T-cell lymphomas may improve our understanding of the tumor microenvironment's pathogenic role in these aggressive lymphomas.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Line, Tumor
  • Cytokines / genetics
  • Cytokines / metabolism
  • GATA3 Transcription Factor / genetics*
  • GATA3 Transcription Factor / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • Interleukin-10 / genetics*
  • Interleukin-10 / metabolism
  • Kaplan-Meier Estimate
  • Lymphoma, T-Cell, Peripheral / genetics*
  • Lymphoma, T-Cell, Peripheral / metabolism
  • Lymphoma, T-Cell, Peripheral / pathology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology
  • Nitriles
  • Pyrazoles / pharmacology
  • Pyrimidines
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Risk Factors
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Th2 Cells / metabolism
  • Th2 Cells / pathology
  • Tumor Microenvironment / genetics*

Substances

  • Cytokines
  • GATA3 Transcription Factor
  • GATA3 protein, human
  • Nitriles
  • Pyrazoles
  • Pyrimidines
  • Interleukin-10
  • ruxolitinib