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

Research output: Contribution to journalArticleResearchpeer-review

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

Cite this

Bachmann, Petra S. ; Piazza, Rocco G. ; Janes, Mary E. ; Wong, Nicholas C. ; Davies, Carwyn ; Mogavero, Angela ; Bhadri, Vivek A. ; Szymanska, Barbara ; Geninson, Greta ; Magistroni, Vera ; Cazzaniga, Giovanni ; Biondi, Andrea ; Miranda-Saavedra, Diego ; Göttgens, Berthold ; Saffery, Richard ; Craig, Jeffrey M. ; Marshall, Glenn M. ; Gambacorti-Passerini, Carlo ; Pimanda, John E. ; Lock, Richard B. / Epigenetic silencing of BIM in glucocorticoid poor-responsive pediatric acute lymphoblastic leukemia, and its reversal by histone deacetylase inhibition. In: Blood. 2010 ; Vol. 116, No. 16. pp. 3013-3022.
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title = "Epigenetic silencing of BIM in glucocorticoid poor-responsive pediatric acute lymphoblastic leukemia, and its reversal by histone deacetylase inhibition",
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.",
author = "Bachmann, {Petra S.} and Piazza, {Rocco G.} and Janes, {Mary E.} and Wong, {Nicholas C.} and Carwyn Davies and Angela Mogavero and Bhadri, {Vivek A.} and Barbara Szymanska and Greta Geninson and Vera Magistroni and Giovanni Cazzaniga and Andrea Biondi and Diego Miranda-Saavedra and Berthold G{\"o}ttgens and Richard Saffery and Craig, {Jeffrey M.} and Marshall, {Glenn M.} and Carlo Gambacorti-Passerini and Pimanda, {John E.} and Lock, {Richard B.}",
year = "2010",
month = "10",
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doi = "10.1182/blood-2010-05-284968",
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Bachmann, PS, Piazza, RG, Janes, ME, Wong, NC, Davies, C, Mogavero, A, Bhadri, VA, Szymanska, B, Geninson, G, Magistroni, V, Cazzaniga, G, Biondi, A, Miranda-Saavedra, D, Göttgens, B, Saffery, R, Craig, JM, Marshall, GM, Gambacorti-Passerini, C, Pimanda, JE & Lock, RB 2010, 'Epigenetic silencing of BIM in glucocorticoid poor-responsive pediatric acute lymphoblastic leukemia, and its reversal by histone deacetylase inhibition' Blood, vol. 116, no. 16, pp. 3013-3022. https://doi.org/10.1182/blood-2010-05-284968

Epigenetic silencing of BIM in glucocorticoid poor-responsive pediatric acute lymphoblastic leukemia, and its reversal by histone deacetylase inhibition. / Bachmann, Petra S.; Piazza, Rocco G.; Janes, Mary E.; Wong, Nicholas C.; Davies, Carwyn; Mogavero, Angela; Bhadri, Vivek A.; Szymanska, Barbara; Geninson, Greta; Magistroni, Vera; Cazzaniga, Giovanni; Biondi, Andrea; Miranda-Saavedra, Diego; Göttgens, Berthold; Saffery, Richard; Craig, Jeffrey M.; Marshall, Glenn M.; Gambacorti-Passerini, Carlo; Pimanda, John E.; Lock, Richard B.

In: Blood, Vol. 116, No. 16, 21.10.2010, p. 3013-3022.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Epigenetic silencing of BIM in glucocorticoid poor-responsive pediatric acute lymphoblastic leukemia, and its reversal by histone deacetylase inhibition

AU - Bachmann, Petra S.

AU - Piazza, Rocco G.

AU - Janes, Mary E.

AU - Wong, Nicholas C.

AU - Davies, Carwyn

AU - Mogavero, Angela

AU - Bhadri, Vivek A.

AU - Szymanska, Barbara

AU - Geninson, Greta

AU - Magistroni, Vera

AU - Cazzaniga, Giovanni

AU - Biondi, Andrea

AU - Miranda-Saavedra, Diego

AU - Göttgens, Berthold

AU - Saffery, Richard

AU - Craig, Jeffrey M.

AU - Marshall, Glenn M.

AU - Gambacorti-Passerini, Carlo

AU - Pimanda, John E.

AU - Lock, Richard B.

PY - 2010/10/21

Y1 - 2010/10/21

N2 - 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.

AB - 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.

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U2 - 10.1182/blood-2010-05-284968

DO - 10.1182/blood-2010-05-284968

M3 - Article

VL - 116

SP - 3013

EP - 3022

JO - Blood

JF - Blood

SN - 0006-4971

IS - 16

ER -