title: Epigenetic deregulation in pediatric acute lymphoblastic leukemia.
abstract: Similar to most cancers, genome-wide DNA methylation profiles are commonly altered in pediatric acute lymphoblastic leukemia (ALL); however, recent observations highlight that a large portion of malignancy-associated DNA methylation alterations are not accompanied by related gene expression changes. By analyzing and integrating the methylome and transcriptome profiles of pediatric B-cell ALL cases and primary tissue controls, we report 325 genes hypermethylated and downregulated and 45 genes hypomethylated and upregulated in pediatric B-cell ALL, irrespective of subtype. Repressed cation channel subunits and cAMP signaling activators and transducers are overrepresented, potentially indicating a reduced cellular potential to receive and propagate apoptotic signals. Furthermore, we report specific DNA methylation alterations with concurrent gene expression changes within individual ALL subtypes. The ETV6-RUNX1 translocation was associated with downregulation of ASNS and upregulation of the EPO-receptor, while Hyperdiploid patients (> 50 chr) displayed upregulation of B-cell lymphoma (BCL) members and repression of PTPRG and FHIT. In combination, these data indicate genetically distinct B-cell ALL subtypes contain cooperative epimutations and genome-wide epigenetic deregulation is common across all B-cell ALL subtypes.
authors.affiliation: Murdoch Childrens Research Institute; The University of Melbourne Department of Paediatrics at the Royal Children's Hospital; Victoria, VIC Australia.
authors.forename: Zac
authors.initials: Z
authors.lastname: Chatterton
authors.affiliation: Murdoch Childrens Research Institute; The University of Melbourne Department of Paediatrics at the Royal Children's Hospital; Victoria, VIC Australia.
authors.forename: Leah
authors.initials: L
authors.lastname: Morenos
authors.affiliation: Childrens Cancer Centre; Royal Children's Hospital; Victoria, VIC Australia.
authors.forename: Francoise
authors.initials: F
authors.lastname: Mechinaud
authors.affiliation: Andrew Love Cancer Centre; Deakin University; Victoria, VIC Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Ashley
authors.affiliation: Murdoch Childrens Research Institute; The University of Melbourne Department of Paediatrics at the Royal Children's Hospital; Victoria, VIC Australia.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Craig
authors.affiliation: Murdoch Childrens Research Institute; The University of Melbourne Department of Paediatrics at the Royal Children's Hospital; Victoria, VIC Australia.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sexton-Oates
authors.affiliation: Murdoch Childrens Research Institute; The University of Melbourne Department of Paediatrics at the Royal Children's Hospital; Victoria, VIC Australia.
authors.forename: Minhee S
authors.initials: MS
authors.lastname: Halemba
authors.affiliation: Murdoch Childrens Research Institute; The University of Melbourne Department of Paediatrics at the Royal Children's Hospital; Victoria, VIC Australia.
authors.forename: Mandy
authors.initials: M
authors.lastname: Parkinson-Bates
authors.affiliation: Murdoch Childrens Research Institute; The University of Melbourne Department of Paediatrics at the Royal Children's Hospital; Victoria, VIC Australia.
authors.forename: Jane
authors.initials: J
authors.lastname: Ng
authors.affiliation: New York University Cancer Institute; New York, NY USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Morrison
authors.affiliation: New York University Cancer Institute; New York, NY USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.affiliation: Murdoch Childrens Research Institute; The University of Melbourne Department of Paediatrics at the Royal Children's Hospital; Victoria, VIC Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Saffery
authors.affiliation: Murdoch Childrens Research Institute; The University of Melbourne Department of Paediatrics at the Royal Children's Hospital; Victoria, VIC Australia.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Wong
mesh_terms: D016022:Case-Control Studies; D002648:Child; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
keywords: ALL; B-cell; DNA methylation; acute lymphoblastic leukemia; epigenetics; hematology; leukemia