Human Molecular Genetics Advance Access published online on July 5, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm178
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Expression of SMARCB1 modulates steroid sensitivity in human lymphoblastoid cells: identification of a promoter SNP that alters PARP1 binding and SMARCB1 expression
1 From the Hematological Malignancies Program 2 Department of Pharmaceutical Sciences 3 St. Jude Children's Research Hospital; EA2679 4 Faculte de Medecine de Lille, Pole Recherche, Lille, France; the Hartwell Center for Bioinformatics and Biotechnology 5 St. Jude Children's Research Hospital, Memphis, TN, USA; and the Pharmacogenetics of Anticancer Agents Research Group in the Pharmacogenetics Research Network
* To whom correspondence should be addressed: Dr. William E. Evans, St. Jude Children's Research Hospital, 332 N. Lauderdale St. Memphis, TN 38105, USA, Phone: +1 (901) 495-3301, Fax: +1 (901) 495-2720, E-mail: william.evans{at}stjude.org
Received May 23, 2007; Revised July 2, 2007; Accepted July 2, 2007
Although cure rate of childhood acute lymphoblastic leukemia (ALL) has surpassed 80%, drug resistance remains a major cause of treatment failure. We previously identified a panel of 33 genes differentially expressed in prednisolone sensitive versus resistant ALL cells from newly diagnosed children. Here we used bioinformatics to identify resistance genes most likely to contain single nucleotide polymorphisms (SNPs) in their promoter region. The highest priority gene was SMARCB1, a core member of the SWI/SNF complex which promotes glucocorticoid effects through nucleosome remodeling. We identified several SNPs in the SMARCB1 promoter in lymphoblastoid cells from 90 individuals in the Centre d'Etude du Polymorphisme Humain (CEPH) panel. Among these SNPs, the -228G>T SNP (allele frequency 9.4%) was the only one that significantly increased reporter activity in human ALL cell lines. Furthermore, we identified nuclear protein poly (ADP-ribose) polymerase family, member 1 (PARP1) as a nuclear protein binding to the SMARCB1 promoter and showed that the 228 SNP significantly altered PARP1 binding affinity. The -228G>T SNP altered SMARCB1 mRNA and protein levels in CEPH cells, and a positive association was found between the SMARCB1 mRNA level and both the -228 genotype and prednisolone sensitivity in CEPH cell lines. Finally, knockdown experiments performed in human ALL cell lines confirmed that lower SMARCB1 expression increased prednisolone resistance. In summary, we provide functional evidence that SMARCB1 is involved in prednisolone resistance and identified a promoter SNP that alters the level of SMARCB1 mRNA and protein expression and the binding of PARP1 to the SMARCB1 promoter.
These authors contributed equally
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