title: Zinc finger protein 382 is downregulated by promoter hypermethylation in pediatric acute myeloid leukemia patients.
abstract: Acute myeloid leukemia (AML) is the second-most common form of leukemia in children. Aberrant DNA methylation patterns are characteristic of AML. Zinc finger protein 382 (ZNF382) has been suggested to be a tumor suppressor gene possibly regulated by promoter hypermethylation in various types of human cancer. However, ZNF382 expression and methylation status in pediatric AML is unknown. In the present study, ZNF382 transcription levels were evaluated by quantitative reverse-transcription PCR. Methylation status was investigated by methylation-specific (MSP) PCR and bisulfate genomic sequencing (BGS). The prognostic significance of ZNF382 expression and promoter methylation was assessed in 105 cases of pediatric AML. The array data suggested that the ZNF382 promoter was hypermethylated in the AML cases examined. MSP PCR and BGS analysis revealed that ZNF382 was hypermethylated in leukemia cell lines. Furthermore, treatment with 5-aza-2'-deoxycytidine (5-Aza) upregulated ZNF382 expression in the selected leukemia cell lines. The aberrant methylation of ZNF382 was observed in 10% (2/20) of the control samples compared with 26.7% (28/105) of the AML samples. ZNF382 expression was significantly decreased in the 105 AML patients compared with the controls. Patients with ZNF382 methylation showed lower ZNF382 transcript levels compared with patients exhibiting no methylation. There were no significant differences in clinical characteristics or cytogenetic analysis between the patients with or without ZNF382 methylation. ZNF382 methylation correlated with minimal residual disease (MRD). Kaplan-Meier survival analysis revealed similar survival times in the samples with ZNF382 methylation, and multivariate analysis revealed that ZNF382 methylation was not an independent prognostic factor in pediatric AML. The epigenetic inactivation of ZNF382 by promoter hypermethylation can be observed in AML cell lines and pediatric AML samples. Therefore, our study suggests that ZNF382 may be considered a putative tumor suppressor gene in pediatric AML. However, further studies focusing on the mechanisms responsible for ZNF382 downregulation in pediatric leukemia are required.
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Yan-Fang
authors.initials: YF
authors.lastname: Tao
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Shao-Yan
authors.initials: SY
authors.lastname: Hu
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Lan
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Zhao
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Pei-Fang
authors.initials: PF
authors.lastname: Xiao
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Li-Xiao
authors.initials: LX
authors.lastname: Xu
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Zhi-Heng
authors.initials: ZH
authors.lastname: Li
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, The 5th Hospital of Chinese PLA, Yinchuan, Ningxia, P.R. China.
authors.forename: Xiao-Juan
authors.initials: XJ
authors.lastname: Du
authors.affiliation: Department of Cell and Molecular Biology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, P.R. China.
authors.forename: Li-Chao
authors.initials: LC
authors.lastname: Sun
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: He
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Guang-Hao
authors.initials: GH
authors.lastname: Su
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Li
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Li
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Yun-Yun
authors.initials: YY
authors.lastname: Xu
authors.affiliation: Translational Research Center, Second Hospital, The Second Clinical School, Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ni
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Xing
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Pan
mesh_terms: D000208:Acute Disease; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002648:Child; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D000077209:Decitabine; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D053208:Kaplan-Meier Estimate; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018365:Neoplasm, Residual; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000706:statistics & numerical data; D014157:Transcription Factors / Q000235:genetics*; D020298:U937 Cells
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D014157:Transcription Factors; C116326:ZNF382 protein, human; D000077209:Decitabine; D001374:Azacitidine