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

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Travert, M. | Y.L., Huang | Leval L., De | Martin-Garcia, N. | M.H., Delfau-Larue | Berger, F. | Bosq, J. | Briere, J. | Soulier, J. | Macintyre, E. | Marafioti, T. | Reynies A., De

Edité par CCSD ; American Society of Hematology -

International audience. The pathogenesis of hepatosplenic T-cell lymphoma (HSTL), a rare entity mostly derived from gamma delta T cells and usually with a fatal outcome, remains largely unknown. In this study, HSTL samples (7 gamma delta and 2 alpha beta) 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 gamma delta 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.

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