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

• Published in: Blood Vol. 119; no. 24; pp. 5795 - 5806
• Main Authors: Travert, Marion, Huang, Yenlin, de Leval, Laurence, Martin-Garcia, Nadine, Delfau-Larue, Marie-Helene, Berger, Françoise, Bosq, Jacques, Brière, Josette, Soulier, Jean, MacIntyre, Elizabeth, Marafioti, Teresa, de Reyniès, Aurélien, Gaulard, Philippe
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 14.06.2012; Americain Society of Hematology; American Society of Hematology
• Subjects: Adult; Aged; Base Sequence; Biological and medical sciences; 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; Hematologic and hematopoietic diseases; Hematology; Human health and pathology; Humans; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - metabolism; Isochromosomes - genetics; Life Sciences; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Lymphoma, T-Cell - drug therapy; Lymphoma, T-Cell - genetics; Lymphoma, T-Cell - pathology; Male; Medical sciences; 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; Treatment; Targeting; Hematology; T lymphoma; Digestive system; Targeted therapy; Liver
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2011-12-396150

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.