Journal article
Epigenetic silencing of BIM in glucocorticoid poor-responsive pediatric acute lymphoblastic leukemia, and its reversal by histone deacetylase inhibition
PS Bachmann, RG Piazza, ME Janes, NC Wong, C Davies, A Mogavero, VA Bhadri, B Szymanska, G Geninson, V Magistroni, G Cazzaniga, A Biondi, D Miranda-Saavedra, B Göttgens, R Saffery, JM Craig, GM Marshall, C Gambacorti-Passerini, JE Pimanda, RB Lock
Blood | Published : 2010
Abstract
Glucocorticoids play a critical role in the therapy of lymphoid malignancies, including pediatric acute lymphoblastic leukemia (ALL), although the mechanisms underlying cellular resistance remain unclear. We report glucocorticoid resistance attributable to epigenetic silencing of the BIM gene in pediatric ALL biopsies and xenografts established in immunedeficient mice from direct patient explants as well as a therapeutic approach to reverse resistance in vivo. Glucocorticoid resistance in ALL xenografts was consistently associated with failure to upregulate BIM expression after dexamethasone exposure despite confirmation of a functional glucocorticoid receptor. Although a comprehensive asses..
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Awarded by Medical Research Council
Funding Acknowledgements
This work was supported by the Children's Cancer Institute Australia for Medical Research, a fellowship (R.B.L.) and grants from The Australian National Health and Medical Research Council and the Anthony Rothe Memorial Trust, a University Postgraduate Award from the University of New South Wales (P.S.B.), an Australian Postgraduate Award (C.D.), the Center for Children's Cancer and Blood Disorders, Sydney Children's Hospital (V.A.B.), by a Postgraduate Scholarship from the Leukemia Foundation of Australia (V.A.B.), by the Associazione Italiana Ricerca sul Cancro (AIRC, IG-4637). and by the Italian Prin program-Ministry of University and Research (PRIN-MIUR).