Molecular features of hepatosplenic T-cell lymphoma unravels potential novel therapeutic targets

Blood. 2012 Jun 14;119(24):5795-806. doi: 10.1182/blood-2011-12-396150. Epub 2012 Apr 17.

Abstract

The pathogenesis of hepatosplenic T-cell lymphoma (HSTL), a rare entity mostly derived from γδ T cells and usually with a fatal outcome, remains largely unknown. In this study, HSTL samples (7γδ and 2αβ) and the DERL2 HSTL cell line were subjected to combined gene-expression profiling and array-based comparative genomic hybridization. Compared with other T-cell lymphomas, HSTL had a distinct molecular signature irrespective of TCR cell lineage. Compared with peripheral T-cell lymphoma, not otherwise specified and normal γδ T cells, HSTL overexpressed genes encoding NK-cell-associated molecules, oncogenes (FOS and VAV3), the sphingosine-1-phosphatase receptor 5 involved in cell trafficking, and the tyrosine kinase SYK, whereas the tumor-suppressor gene AIM1 (absent in melanoma 1) was among the most down-expressed. We found highly methylated CpG islands of AIM1 in DERL2 cells, and decitabine treatment induced a significant increase in AIM1 transcripts. Syk was present in HSTL cells and DERL2 cells contained phosphorylated Syk and were sensitive to a Syk inhibitor in vitro. Genomic profiles confirmed recurrent isochromosome 7q (n = 6/9) without alterations at the SYK and AIM1 loci. Our results identify a distinct molecular signature for HSTL and highlight oncogenic pathways that offer rationale for exploring new therapeutic options such as Syk inhibitors and demethylating agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Base Sequence
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Cell Lineage / genetics
  • Chromosome Aberrations
  • Cluster Analysis
  • Crystallins / metabolism
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genes, Neoplasm / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Isochromosomes / genetics
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Lymphoma, T-Cell / drug therapy*
  • Lymphoma, T-Cell / genetics*
  • Lymphoma, T-Cell / pathology
  • Male
  • Membrane Proteins / metabolism
  • Middle Aged
  • Molecular Sequence Data
  • Molecular Targeted Therapy*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, gamma-delta / genetics
  • Splenic Neoplasms / drug therapy*
  • Splenic Neoplasms / genetics*
  • Splenic Neoplasms / pathology
  • Syk Kinase
  • Young Adult

Substances

  • Biomarkers, Tumor
  • CRYBG1 protein, human
  • Crystallins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Receptors, Antigen, T-Cell, alpha-beta
  • Receptors, Antigen, T-Cell, gamma-delta
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase