title: A distinct DNA methylation signature defines pediatric pre-B cell acute lymphoblastic leukemia.
abstract: Pre-B cell acute lymphoblastic leukemia (ALL) is the most prevalent childhood malignancy and remains one of the highest causes of childhood mortality. Despite this, the mechanisms leading to disease remain poorly understood. We asked if recurrent aberrant DNA methylation plays a role in childhood ALL and have defined a genome-scale DNA methylation profile associated with the ETV6-RUNX1 subtype of pediatric ALL. Archival bone marrow smears from 19 children collected at diagnosis and remission were used to derive a disease specific DNA methylation profile. The gene signature was confirmed in an independent cohort of 86 patients. A further 163 patients were analyzed for DNA methylation of a three gene signature. We found that the DNA methylation signature at diagnosis was unique from remission. Fifteen loci were sufficient to discriminate leukemia from disease-free samples and purified CD34+ cells. DNA methylation of these loci was recurrent irrespective of cytogenetic subtype of pre-B cell ALL. We show that recurrent aberrant genomic methylation is a common feature of pre-B ALL, suggesting a shared pathway for disease development. By revealing new DNA methylation markers associated with disease, this study has identified putative targets for development of novel epigenetic-based therapies.
authors.affiliation: Murdoch Childrens Research Institute, Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Wong
authors.forename: David
authors.initials: D
authors.lastname: Ashley
authors.forename: Zac
authors.initials: Z
authors.lastname: Chatterton
authors.forename: Mandy
authors.initials: M
authors.lastname: Parkinson-Bates
authors.forename: Hong Kiat
authors.initials: HK
authors.lastname: Ng
authors.forename: Minhee S
authors.initials: MS
authors.lastname: Halemba
authors.forename: Adam
authors.initials: A
authors.lastname: Kowalczyk
authors.forename: Justin
authors.initials: J
authors.lastname: Bedo
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wang
authors.forename: Katrina
authors.initials: K
authors.lastname: Bell
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Algar
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Craig
authors.forename: Richard
authors.initials: R
authors.lastname: Saffery
mesh_terms: D014408:Biomarkers, Tumor; D002648:Child; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000032:analysis; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D014408:Biomarkers, Tumor; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein