title: ADAMTSL5 and CDH11: putative epigenetic markers for therapeutic resistance in acute lymphoblastic leukemia.
abstract: OBJECTIVE
  DNA hypermethylation has been linked to poor treatment outcome in childhood acute lymphoblastic leukemia (ALL). Genes differentially methylated in the chemoresponsive pre-B-ALL compared to chemoresistant pre-B-ALL cases provide potential prognostic markers.
  
  
  METHODS
  DNA methylation profiles of five B-ALL childhood patients who achieved morphological complete remission (chemoresponsive) and five B-ALL patients who did not (chemoresistant) after induction treatments as well as four normal controls were compared on 27 000 CpG sites microarray chips. Subsequently, methylation-specific polymerase chain reaction (MSP) on selected hypermethylated genes was conducted on an additional 37 chemoresponsive and 9 chemoresistant B-ALL samples and 2 normal controls.
  
  
  RESULTS
  Both methods were found to be highly correlated. Unsupervised principal component analysis showed that the chemotherapy-responsive and -resistant B-ALL patients could be segregated from one another. Selection of segregated genes at high stringency identified two potential genes (CDH11 and ADAMTSL5). MSP analysis on the larger cohort of samples (42 chemoresponsive, 14 chemoresistant B-ALL samples and 6 normal controls) revealed significantly higher rates of hypermethylation in chemoresistant samples for ADAMTSL5 (93 vs. 38%; p = 0.0001) and CDH11 (79% vs. 40%, p < 0.01). All control cases remained unmethylated.
  
  
  CONCLUSIONS
  Chemoresistant B-ALL patients are associated with increased methylation in ADAMTSL5 and CDH11. These findings need to be validated in a larger group of patients, and the functional biological and prognostic significance of differential methylation needs to be studied further.
authors.affiliation: a Immunology Unit, Department of Pathology , UPM, Serdang , Selangor , Malaysia.
authors.forename: Maha
authors.initials: M
authors.lastname: Abdullah
authors.affiliation: b Department of Pathology, Faculty of Medicine , UKM Medical Centre , Kuala Lumpur , Malaysia.
authors.forename: Chee Wei
authors.initials: CW
authors.lastname: Choo
authors.affiliation: c Department of Paediatrics, Faculty of Medicine , UKM Medical Centre , Kuala Lumpur , Malaysia.
authors.forename: Hamidah
authors.initials: H
authors.lastname: Alias
authors.affiliation: d Institute of Paediatrics, Hospital Kuala Lumpur , Kuala Lumpur , Malaysia.
authors.forename: Eni Juraidah
authors.initials: EJ
authors.lastname: Abdul Rahman
authors.affiliation: d Institute of Paediatrics, Hospital Kuala Lumpur , Kuala Lumpur , Malaysia.
authors.forename: Hishamshah
authors.initials: H
authors.lastname: Mohd Ibrahim
authors.affiliation: e UKM Medical Molecular Biology Institute , Kuala Lumpur , Malaysia.
authors.forename: Rahman
authors.initials: R
authors.lastname: Jamal
authors.affiliation: b Department of Pathology, Faculty of Medicine , UKM Medical Centre , Kuala Lumpur , Malaysia.
authors.forename: Noor Hamidah
authors.initials: NH
authors.lastname: Hussin
mesh_terms: D000071096:ADAMTS Proteins / Q000235:genetics*; D000293:Adolescent; D000704:Analysis of Variance; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D015820:Cadherins / Q000235:genetics*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D019295:Computational Biology; D018899:CpG Islands; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; C086960:osteoblast cadherin; D000071096:ADAMTS Proteins; C581035:ADAMTSL5 protein, human
keywords: Acute lymphoblastic leukemia (ALL); epigenetic marker; methylation