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

journal contribution
posted on 2010-10-21, 00:00 authored by 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 CraigJeffrey Craig, Glenn M Marshall, Carlo Gambacorti-Passerini, John E Pimanda, Richard B Lock
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.

History

Journal

Blood

Volume

116

Pagination

3013-3022

Location

Washington, D.C.

eISSN

1528-0020

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal

Copyright notice

2010, The American Society of Hematology

Issue

16

Publisher

American Society of Hematology