Epigenetic silencing of BIM in glucocorticoid poor-responsive pediatric acute lymphoblastic leukemia, and its reversal by histone deacetylase inhibition

Petra S. Bachmann, Rocco G. Piazza, Mary E. Janes, Nicholas C. Wong, Carwyn Davies, Angela Mogavero, Vivek A. Bhadri, Barbara Szymanska, Greta Geninson, Vera Magistroni, Giovanni Cazzaniga, Andrea Biondi, Diego Miranda-Saavedra, Berthold Göttgens, Richard Saffery, Jeffrey M. Craig, Glenn M. Marshall, Carlo Gambacorti-Passerini, John E. Pimanda, Richard B. Lock

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84 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)3013-3022
Number of pages10
JournalBlood
Volume116
Issue number16
DOIs
Publication statusPublished - 21 Oct 2010
Externally publishedYes

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