By using a combination of genomic and expression profiling (Affymetrix GeneChip Mapping 10k Xba131 and U133 set), we had previously analysed a series of 26 mantle cell lymphoma (MCL) samples to identify regions containing genes that might be relevant to MCL pathogenesis and that could represent new therapeutic targets (

Rinaldi et al, Ann Oncol 2005; vol. 16 suppl. 5, abstract 447
). Of interest, one MCL cell line showed a genomic amplification of 9q22 with concomitant over-expression of SYK, mapped within the region. SYK is a tyrosine kinase involved in B cell receptor signaling, a pathway that is believed to play a major role in B cell lymphoma growth and survival. Western blotting experiments and FISH analysis confirmed the over-expression of SYK and the presence of extra-copies of SYK, respectively. Immunohistochemistry on twelve aggressive lymphomas [MCL and diffuse large B cell lymphomas (DLBCL)] confirmed that SYK is over-expressed in a subset of lymphomas. Based upon all these data, we treated seven established human lymphoma cell lines (four MCL, three DLBCL) with increasing doses of piceatannol (Sigma), a SYK inhibitor. All, but one, cell lines showed arrest of cell proliferation. The JeKo-1 and SU-DHL-6 (MCL and DLBCL) cell lines showed an IC50 of less than 10 μM after 72 hr of drug exposure; four cell lines had an IC50 between 30–50 μM. The two cell lines with a high-sensitivity to SYK inhibition had a constitutively high expression of SYK due to DNA gain, as shown by Western blotting and FISH. A high percentage of necrotic and apoptotic cells (39%) has been shown in JeKo-1 by Annexin V staining. Further, in vitro analyses and more extensive immunohistochemistry and FISH on MCL and DLBCL clinical samples (using tissue microarrays) are under way to elucidate the mechanism of action of cytotoxicity and the clinical relevance of SYK DNA amplification. In conclusion, our in vitro data indicate SYK inhibition as a new therapeutic target for the treatment of a subset of aggressive lymphomas, over-expressing SYK. SYK inhibitors are already in clinical development for treatment of asthma. Work partially supported by the Krebsforschung Schweiz and the Swiss Group for Clinical Research (SAKK).

Topics:
b-lymphocytes, lymphoma, protein tyrosine kinase, diffuse large b-cell lymphoma, b-cell lymphomas, western blotting, annexin a5, asthma, cytotoxicity, dna

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2005, The American Society of Hematology
2005
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