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

Marion Travert, Yenlin Huang, Laurence De Leval, Nadine Martin-Garcia, Marie Helene Delfau-Larue, Françoise Berger, Jacques Bosq, Josette Brière, Jean Soulier, Elizabeth MacIntyre, Teresa Marafioti, Aurélien De Reyniès, Philippe Gaulard*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

100 Scopus citations

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 downexpressed. 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.

Original languageEnglish
Pages (from-to)5795-5806
Number of pages12
JournalBlood
Volume119
Issue number24
DOIs
StatePublished - 14 06 2012
Externally publishedYes

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