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Polo‐like‐kinase 1 (PLK1) as a molecular target to overcome SYK‐mediated resistance of B‐lineage acute lymphoblastic leukaemia cells to oxidative stress
Author(s) -
Uckun Fatih M.,
Ozer Zahide,
Qazi Sanjive,
TuelAhlgren Lisa,
Mao Chen
Publication year - 2010
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2009.07983.x
Subject(s) - syk , cancer research , tyrosine kinase , biology , kinase , apoptosis , programmed cell death , protein kinase b , microbiology and biotechnology , signal transduction , biochemistry
Summary SYK tyrosine kinase has emerged as a master regulator of cellular resistance to oxidative stress (OS) by mediating the activation of the anti‐apoptotic nuclear factor κB and phosphatidylinositol‐3 kinase/AKT pathways after OS exposure. Here, we present unprecedented experimental evidence that polo‐like kinase 1 (PLK1) is the upstream regulator of SYK in B‐lineage acute lymphoblastic leukaemia (ALL) cells. Selective inhibition of PLK‐1 with the leflunomide metabolite analogue α‐cyano‐β‐hydroxy‐β‐methyl‐ N ‐[4‐(trifluoromethoxy) phenyl]‐propenamide/LFM‐A12 abolished the resistance of B‐lineage ALL cells to OS by preventing the activation of the anti‐apoptotic SYK signal transduction pathway. Notably, LFM‐A12 treatments at non‐cytotoxic concentrations resulted in marked augmentation of clonogenic death in resistant human B‐lineage ALL cell lines challenged with OS. Further, LFM‐A12 augmented OS‐induced apoptosis of chemotherapy‐resistant primary leukaemic cells from relapsed B‐lineage ALL patients in vitro and markedly potentiated the in vivo anti‐leukaemic activity of total body irradiation (TBI) against leukaemia‐initiating cells in severe combined immunodeficient mouse xenograft models of B‐lineage ALL. This study is the first to identify PLK1 as a regulator of SYK tyrosine kinase and a molecular target to overcome SYK‐mediated resistance of B‐lineage ALL cells to OS.