ORCID Profile
0000-0001-6058-515X
Current Organisation
Università degli Studi di Milano-Bicocca
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Publisher: Ferrata Storti Foundation (Haematologica)
Date: 30-04-2016
Publisher: Springer Science and Business Media LLC
Date: 17-06-2019
Publisher: Massachusetts Medical Society
Date: 07-11-2013
Publisher: American Society of Hematology
Date: 21-10-2010
DOI: 10.1182/BLOOD-2010-05-284968
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.
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1593/NEO.121784
No related grants have been discovered for CARLO GAMBACORTI PASSERINI.