The SWI/SNF chromatin-remodeling complex and glucocorticoid resistance in acute lymphoblastic leukemia.
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 [LC(50)] = 277 microM) than in control shRNA-transfected cells (LC(50) = 174 microM, difference = 103 microM, 95% confidence interval of the difference = 100 to 106 microM; P < .001, t test).


CONCLUSIONS
Decreased expression of as many as three subunits of the SWI/SNF complex appears to be associated with glucocorticoid resistance in primary ALL cells.
Pottier
Nicolas
N
Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN, USA.
Yang
Wenjian
W
Assem
Mahfoud
M
Panetta
John C
JC
Pei
Deqing
D
Paugh
Steven W
SW
Cheng
Cheng
C
Den Boer
Monique L
ML
Relling
Mary V
MV
Pieters
Rob
R
Evans
William E
WE
Cheok
Meyling H
MH
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004265:DNA Helicases / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D019169:Jurkat Cells; D016086:Lentivirus; D016014:Linear Models; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism*; D011239:Prednisolone / Q000627:therapeutic use*; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014161:Transduction, Genetic
D018931:Antineoplastic Agents, Hormonal; D002868:Chromosomal Proteins, Non-Histone; D005938:Glucocorticoids; D009687:Nuclear Proteins; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; D011239:Prednisolone; C084108:SMARCA4 protein, human; D004265:DNA Helicases