title: NF-kappa B mediated up-regulation of CCCTC-binding factor in pediatric acute lymphoblastic leukemia.
abstract: BACKGROUND
  Acute lymphoblastic leukemia (ALL) is the most frequently occurring malignant neoplasm in children. Despite advances in treatment and outcomes for ALL patients, the pathogenesis of the disease remains unclear. Microarray analysis of samples from 100 Chinese children with ALL revealed the up-regulation of CTCF (CCCTC binding factor). CTCF is a highly conserved 11-zinc finger protein that is involved in many human cancers; however, the biological function of CTCF in pediatric ALL is unknown.
  
  
  METHODS
  The expression patterns of CTCF were evaluated in matched newly diagnosed (ND), complete remission (CR), and relapsed (RE) bone marrow samples from 28 patients. The potential oncogenic mechanism of CTCF and related pathways in leukemogenesis were investigated in leukemia cell lines.
  
  
  RESULTS
  We identified significant up-regulation of CTCF in the ND samples. Importantly, the expression of CTCF returned to normal levels after CR but rebounded in the RE samples. In the pre-B ALL cell line Nalm-6, siRNA-mediated silencing of CTCF expression promoted cell apoptosis and reduced cell proliferation; accordingly, over-expression of a cDNA encoding full-length CTCF protected cells from apoptosis and enhanced cell proliferation. Furthermore, inhibition or activation of the nuclear factor-kappa B (NF-κB) pathway resulted in marked variations in the levels of CTCF mRNA and protein in leukemic cells, indicating that CTCF may be involved downstream of the NF-κB pathway. Moreover, inhibition of the NF-κB pathway increased cell apoptosis, which was partially rescued by ectopic over-expression of CTCF, suggesting that CTCF may play a significant role in the anti-apoptotic pathway mediated by NF-κB.
  
  
  CONCLUSIONS
  Our results indicate that CTCF serves as both an anti-apoptotic factor and a proliferative factor in leukemic cells. It potentially contributes to leukemogenesis through the NF-κB pathway in pediatric ALL patients.
authors.forename: Han
authors.initials: H
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.forename: Huacheng
authors.initials: H
authors.lastname: He
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Xiao
authors.initials: X
authors.lastname: Liu
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Zhao
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.forename: Mei
authors.initials: M
authors.lastname: Mei
authors.affiliation: Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics, Ministry of Education; Key Laboratory of Major Diseases in Children, Ministry of Education; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, 56 Nanlishi Road, Beijing, 100045, China. slbao@genetics.ac.cn.
authors.forename: Shilai
authors.initials: S
authors.lastname: Bao
authors.forename: Huyong
authors.initials: H
authors.lastname: Zheng
mesh_terms: D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D000076246:CCCTC-Binding Factor; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007223:Infant; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D016328:NF-kappa B; D012097:Repressor Proteins