title: Molecular features of hepatosplenic T-cell lymphoma unravels potential novel therapeutic targets.
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.
authors.affiliation: Inserm U955, Créteil, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Travert
authors.forename: Yenlin
authors.initials: Y
authors.lastname: Huang
authors.forename: Laurence
authors.initials: L
authors.lastname: de Leval
authors.forename: Nadine
authors.initials: N
authors.lastname: Martin-Garcia
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Delfau-Larue
authors.forename: Françoise
authors.initials: F
authors.lastname: Berger
authors.forename: Jacques
authors.initials: J
authors.lastname: Bosq
authors.forename: Josette
authors.initials: J
authors.lastname: Brière
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Macintyre
authors.forename: Teresa
authors.initials: T
authors.lastname: Marafioti
authors.forename: Aurélien
authors.initials: A
authors.lastname: de Reyniès
authors.forename: Philippe
authors.initials: P
authors.lastname: Gaulard
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D019070:Cell Lineage / Q000235:genetics; D002869:Chromosome Aberrations; D016000:Cluster Analysis; D003459:Crystallins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018404:Isochromosomes / Q000235:genetics; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics; D013160:Splenic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D000072377:Syk Kinase; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C105445:CRYBG1 protein, human; D003459:Crystallins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase