GC耐药淋巴细胞的NFKB调节.pdfVIP

N l L N a A R R 1 A A K G C N 1 l l t r t u a u d G t g g s r i l a F m t 0 dLeukemia Research 34 (2010) 1366–1373 Contents lists available at ScienceDirect Leukemia Research journa l homepage: www.e lsev ier .com/ locate / leukres FB modulators in a model of glucocorticoid resistant, childhood acute ymphoblastic leukemia indsay Nicholson, Andrew G. Hall, Christopher P. Redfern, Julie Irving ? orthern Institute for Cancer Research, Newcastle University, Paul O’Gorman Building, Framlington Place, Newcastle upon Tyne, Tyne and Wear, NE2 4HH, UK r t i c l e i n f o rticle history: eceived 23 October 2009 eceived in revised form 9 December 2009 ccepted 19 December 2009 a b s t r a c t Glucocorticoids (GCs) are pivotal agents in the treatment of childhood acute lymphoblastic leukaemia (ALL) but themolecular basis of GC-resistance remains unclear. Expression-array studies have shown that commonly upregulated genes associated with GC-sensitivity include GR, glucocorticoid-induced leucine zipper (GILZ) and IB, which all negatively interact with components of the pro-survival NFB pathwayvailable online 27 January 2010 eywords: lucocorticoid resistance hildhood acute lymphoblastic leukaemia and therefore may be critical determinants of GC-sensitivity. We have investigated these regulators and their effect onNFB activity in GC-resistant descendents of the B-lineage ALL cell line, PreB 697.We show that while differential up regulation of the modulators (GILZ, GR and IB) was demonstrated in GC- sensitive compared to GC-resistant sub-lines, this was not coupled with altered nuclear translocation or functionality of theRelA, p50or c-Rel subunits ofNFB. Thus, GC-resistance in thePreB697 cell linemodel , how l pathFB is not mediated by NFB proteins on other surviva . Introduction Glucocorticoids are central to the treatment regime of all ymphoid malignancies, including childhood acute lymphoblastic eukaemia (ALL), due to their ability to induce apoptosis in imma- ure lymph