title: Genomic and expression profiling identifies the B-cell associated tyrosine kinase Syk as a possible therapeutic target in mantle cell lymphoma.
abstract: Among B-cell lymphomas mantle cell lymphoma (MCL) has the worst prognosis. By using a combination of genomic and expression profiling (Affymetrix GeneChip Mapping 10k Xba131 and U133 set), we analysed 26 MCL samples to identify genes relevant to MCL pathogenesis and that could represent new therapeutic targets. Recurrent genomic deletions and gains were detected. Genes were identified as overexpressed in regions of DNA gain on 3q, 6p, 8q, 9q, 16p and 18q, including the cancer genes BCL2 and MYC. Among the transcripts with high correlation between DNA and RNA, we identified SYK, a tyrosine kinase involved in B-cell receptor signalling. SYK was amplified at DNA level, as validated by fluorescence in situ hybridisation (FISH) analysis, and overexpressed at both RNA and protein levels in the JeKo-1 cell line. Low-level amplification, with protein overexpression of Syk was demonstrated by FISH in a small subset of clinical samples. After treatment with low doses of the Syk inhibitor piceatannol, cell proliferation arrest and apoptosis were induced in the cell line overexpressing Syk, while cells expressing low levels of Syk were much less sensitive. A combination of genomic and expression profiling suggested Syk inhibition as a new therapeutic strategy to be explored in lymphomas.
authors.affiliation: Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rinaldi
authors.forename: Ivo
authors.initials: I
authors.lastname: Kwee
authors.forename: Monica
authors.initials: M
authors.lastname: Taborelli
authors.forename: Cristina
authors.initials: C
authors.lastname: Largo
authors.forename: Silvia
authors.initials: S
authors.lastname: Uccella
authors.forename: Vittoria
authors.initials: V
authors.lastname: Martin
authors.forename: Giulia
authors.initials: G
authors.lastname: Poretti
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Calabrese
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Luca
authors.initials: L
authors.lastname: Baldini
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Pruneri
authors.forename: Carlo
authors.initials: C
authors.lastname: Capella
authors.forename: Emanuele
authors.initials: E
authors.lastname: Zucca
authors.forename: Finbarr E
authors.initials: FE
authors.lastname: Cotter
authors.forename: Juan C
authors.initials: JC
authors.lastname: Cigudosa
authors.forename: Carlo V
authors.initials: CV
authors.lastname: Catapano
authors.forename: Maria G
authors.initials: MG
authors.lastname: Tibiletti
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000201:enzymology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000235:genetics; D004792:Enzyme Precursors / Q000235:genetics*; D017353:Gene Deletion; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins; D020522:Lymphoma, Mantle-Cell / Q000201:enzymology / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D012334:RNA, Neoplasm / Q000235:genetics; D013267:Stilbenes / Q000494:pharmacology; D000072377:Syk Kinase; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D013267:Stilbenes; C041525:3,3',4,5'-tetrahydroxystilbene; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase