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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Antineoplastic Agents, Hormonal / pharmacology
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Antineoplastic Agents, Hormonal / therapeutic use
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Apoptosis Regulatory Proteins / genetics*
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Bcl-2-Like Protein 11
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Child
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Dexamethasone / pharmacology
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Dexamethasone / therapeutic use
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Drug Resistance, Neoplasm* / drug effects
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Gene Silencing*
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Genetic Loci
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Glucocorticoids / pharmacology
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Glucocorticoids / therapeutic use*
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Histone Deacetylase Inhibitors / pharmacology
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Histone Deacetylase Inhibitors / therapeutic use*
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Histone Deacetylases / metabolism
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Humans
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Hydroxamic Acids / pharmacology
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Hydroxamic Acids / therapeutic use
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Membrane Proteins / genetics*
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Mice
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Mice, SCID
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / enzymology
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Proto-Oncogene Proteins / genetics*
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Vorinostat
Substances
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Antineoplastic Agents
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Antineoplastic Agents, Hormonal
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Glucocorticoids
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Membrane Proteins
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Proto-Oncogene Proteins
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Vorinostat
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Dexamethasone
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Histone Deacetylases