Genomic and expression profiling identifies the B-cell associated tyrosine kinase Syk as a possible therapeutic target in mantle cell lymphoma.
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.
Rinaldi
Andrea
A
Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
Kwee
Ivo
I
Taborelli
Monica
M
Largo
Cristina
C
Uccella
Silvia
S
Martin
Vittoria
V
Poretti
Giulia
G
Gaidano
Gianluca
G
Calabrese
Giuseppe
G
Martinelli
Giovanni
G
Baldini
Luca
L
Pruneri
Giancarlo
G
Capella
Carlo
C
Zucca
Emanuele
E
Cotter
Finbarr E
FE
Cigudosa
Juan C
JC
Catapano
Carlo V
CV
Tibiletti
Maria G
MG
Bertoni
Francesco
F
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
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