Article: article from journal or magazin.
Molecular features of hepatosplenic T-cell lymphoma unravels potential novel therapeutic targets.
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
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.
Adult, Aged, Base Sequence, 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, Lymphoma, T-Cell/drug therapy, Lymphoma, T-Cell/genetics, 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, Tumor Markers, Biological/genetics, Tumor Markers, Biological/metabolism, Young Adult
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