title: Epigenetic silencing of BIM in glucocorticoid poor-responsive pediatric acute lymphoblastic leukemia, and its reversal by histone deacetylase inhibition.
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 immune-deficient 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 up-regulate BIM expression after dexamethasone exposure despite confirmation of a functional glucocorticoid receptor. Although a comprehensive assessment of BIM CpG island methylation revealed no consistent changes, glucocorticoid resistance in xenografts and patient biopsies significantly correlated with decreased histone H3 acetylation. Moreover, the histone deacetylase inhibitor vorinostat relieved BIM repression and exerted synergistic antileukemic efficacy with dexamethasone in vitro and in vivo. These findings provide a novel therapeutic strategy to reverse glucocorticoid resistance and improve outcome for high-risk pediatric ALL.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Petra S
authors.initials: PS
authors.lastname: Bachmann
authors.forename: Rocco G
authors.initials: RG
authors.lastname: Piazza
authors.forename: Mary E
authors.initials: ME
authors.lastname: Janes
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Wong
authors.forename: Carwyn
authors.initials: C
authors.lastname: Davies
authors.forename: Angela
authors.initials: A
authors.lastname: Mogavero
authors.forename: Vivek A
authors.initials: VA
authors.lastname: Bhadri
authors.forename: Barbara
authors.initials: B
authors.lastname: Szymanska
authors.forename: Greta
authors.initials: G
authors.lastname: Geninson
authors.forename: Vera
authors.initials: V
authors.lastname: Magistroni
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cazzaniga
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.forename: Diego
authors.initials: D
authors.lastname: Miranda-Saavedra
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
authors.forename: Richard
authors.initials: R
authors.lastname: Saffery
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Craig
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
authors.forename: John E
authors.initials: JE
authors.lastname: Pimanda
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D002648:Child; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D020868:Gene Silencing; D056426:Genetic Loci; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D016513:Mice, SCID; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D005938:Glucocorticoids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D000077337:Vorinostat; D003907:Dexamethasone; D006655:Histone Deacetylases