Epigenetic silencing of BIM in glucocorticoid poor-responsive pediatric acute lymphoblastic leukemia, and its reversal by histone deacetylase inhibition.
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.
Bachmann
Petra S
PS
Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
Piazza
Rocco G
RG
Janes
Mary E
ME
Wong
Nicholas C
NC
Davies
Carwyn
C
Mogavero
Angela
A
Bhadri
Vivek A
VA
Szymanska
Barbara
B
Geninson
Greta
G
Magistroni
Vera
V
Cazzaniga
Giovanni
G
Biondi
Andrea
A
Miranda-Saavedra
Diego
D
Göttgens
Berthold
B
Saffery
Richard
R
Craig
Jeffrey M
JM
Marshall
Glenn M
GM
Gambacorti-Passerini
Carlo
C
Pimanda
John E
JE
Lock
Richard B
RB
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
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