Journal of the National Cancer Institute Advance Access originally published online on December 9, 2008
JNCI Journal of the National Cancer Institute 2008 100(24):1792-1803; doi:10.1093/jnci/djn416
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author 2008. Published by Oxford University Press.
ARTICLES |
The SWI/SNF Chromatin-Remodeling Complex and Glucocorticoid Resistance in Acute Lymphoblastic Leukemia
Affiliations of authors: Hematological Malignancies Program (NP, WY, JCP, SWP, MVR, WEE, MHC), Department of Pharmaceutical Sciences (NP, WY, MA, JCP, SWP, MVR, WEE, MHC), and Department of Biostatistics (DP, CC), St. Jude Children’s Research Hospital, Memphis, TN; EA2679, Faculté de Médecine de Lille, Pôle Recherche (NP), INSERM U837 (MHC), Lille, France; Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Erasmus University Medical Center Rotterdam, the Netherlands (MLDB, RP); and Pharmacogenetics of Anticancer Agents Research Group in the Pharmacogenetics Research Network (MVR, WEE)
Correspondence to: Meyling H. Cheok, PhD, Jean-Pierre Aubert Center, INSERM U837, Institute for Cancer Research in Lille, Genomics Core, 1, Place de Verdun, 59045 Lille cedex, France (e-mail: meyling.cheok{at}inserm.fr).
Background: Glucocorticoids are used in the curative treatment of acute lymphoblastic leukemia (ALL). Resistance to glucocorticoids is an important adverse prognostic factor in newly diagnosed ALL patients but its mechanism is unknown. Because SWI/SNF complex–mediated chromatin remodeling is required for glucocorticoid transcriptional activity in vitro, we investigated whether expression of subunits of the SWI/SNF complex was related to glucocorticoid resistance in ALL.
Methods: Gene expression and in vitro sensitivity to prednisolone and dexamethasone were assessed in a training set of primary ALL cells from 177 children with newly diagnosed ALL and a validation set of cells from an independent cohort of 95 ALL patients. The global test method was used to select pathways whose genes were associated with drug sensitivity. Genes involved in chromatin remodeling were identified by use of the Gene Ontology database. Short hairpin RNA (shRNA) was used to knock down mRNA expression of SMARCA4 in glucocorticoid-sensitive Jurkat human ALL cells. Spearman rank correlation, multiple linear regression, and logistic regression were used to investigate associations between gene expression and glucocorticoid sensitivity. All statistical tests were two-sided.
Results: Statistically significant associations between decreased expression in ALL cells of genes for core subunits of the SWI/SNF complex—SMARCA4, ARID1A, and SMARCB1—and resistance to prednisolone and dexamethasone were identified in the training cohort. In the validation cohort, expression of SMARCA4 (P < .001 and r = –0.43), ARID1A (P = .016 and r = –0.29), and SMARCB1 (P = .019 and r = –0.29) in ALL cells was statistically significantly associated with dexamethasone sensitivity, and SMARCA4 expression (P = .018 and r = –0.28) was statistically significantly associated with prednisolone sensitivity. Prednisolone resistance was higher in SMARCA4 shRNA-transfected Jurkat cells (drug concentration lethal to 50% of the leukemia cells [LC50] = 277 µM) than in control shRNA-transfected cells (LC50 = 174 µM, difference = 103 µM, 95% confidence interval of the difference = 100 to 106 µM; P < .001, t test).
Conclusion: Decreased expression of as many as three subunits of the SWI/SNF complex appears to be associated with glucocorticoid resistance in primary ALL cells.
| CONTEXT AND CAVEATS Prior knowledge Glucocorticoids are a curative treatment for acute lymphoblastic leukemia (ALL), and patients who develop resistance to glucocorticoid treatment have poor prognosis. SWI/SNF complex–mediated chromatin remodeling is required for glucocorticoid transcriptional activity in vitro. Study design Associations between expression of genes encoding components of the SWI/SNF complex and sensitivity to prednisolone and dexamethasone were studied in ALL cells from a training cohort and an independent validation cohort of children with newly diagnosed ALL. RNA interference was used to reduce mRNA expression of SMARCA4 in glucocorticoid-sensitive Jurkat human ALL cells. Contribution ALL cells from every patient studied expressed only SMARCA4 as the catalytic subunit of the SWI/SNF complex; none expressed SMARCA2, the alternate catalytic component. Expression of genes for three components of the SWI/SNF complex (SMARCA4, ARID1A, and SMARCB1) in ALL cells was statistically significantly associated with dexamethasone sensitivity, and expression of one component (SMARCA4) was statistically significantly associated with prednisolone sensitivity. Decreased SMARCA4 expression in Jurkat cells was associated with prednisolone resistance. Implications Future studies should further investigate the association between subunits of the SWI/SNF complex and glucocorticoid resistance in ALL patients. Limitations Glucocorticoid resistance is probably a multigenic phenomenon and may involve additional genes not investigated in this study. The sample size of ALL patients was relatively small, especially of the St. Jude validation cohort. From the Editors
|
Manuscript received June 17, 2008; revised September 19, 2008; accepted October 15, 2008.
Related Article in JNCI
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2008 100: 1741.
This article has been cited by other articles:
|
|
 |
|
  B. Weissman and K. E. Knudsen Hijacking the Chromatin Remodeling Machinery: Impact of SWI/SNF Perturbations in Cancer Cancer Res., November 1, 2009; 69(21): 8223 - 8230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wang, C. G. Sansam, C. S. Thom, D. Metzger, J. A. Evans, P. T.L. Nguyen, and C. W.M. Roberts Oncogenesis Caused by Loss of the SNF5 Tumor Suppressor Is Dependent on Activity of BRG1, the ATPase of the SWI/SNF Chromatin Remodeling Complex Cancer Res., October 15, 2009; 69(20): 8094 - 8101. [Abstract] [Full Text] [PDF]
|
|