Authors: Nicholas C. Wong, David Ashley, Zac Chatterton, Mandy Parkinson-Bates, Hong Kiat Ng, Minhee S. Halemba, Adam Kowalczyk, Justin Bedo, Qiao Wang, Katrina Bell, Elizabeth Algar, Jeffrey M Craig and Richard Saffery

Nicholas C. Wong

Corresponding author: nick.wong@mcri.edu.au
Murdoch Childrens Research Institute; Department of Paediatrics; The University of Melbourne; Royal Children’s Hospital; Melbourne, VIC Australia
These authors contributed equally.

David Ashley

Andrew Love Cancer Centre; Deakin University; Waum Ponds, VIC Australia
These authors contributed equally.

Zac Chatterton

Murdoch Childrens Research Institute; Department of Paediatrics; The University of Melbourne; Royal Children’s Hospital; Melbourne, VIC Australia
These authors contributed equally.

Mandy Parkinson-Bates

Murdoch Childrens Research Institute; Royal Children’s Hospital; Parkville, VIC Australia

Hong Kiat Ng

Murdoch Childrens Research Institute; Royal Children’s Hospital; Parkville, VIC Australia

Minhee S. Halemba

Murdoch Childrens Research Institute; Royal Children’s Hospital; Parkville, VIC Australia

Adam Kowalczyk

NICTA; Victoria Research Laboratory; Department of Computer Science and Software Engineering; The University of Melbourne; Melbourne, VIC Australia

Justin Bedo

NICTA; Victoria Research Laboratory; Department of Computer Science and Software Engineering; The University of Melbourne; Melbourne, VIC Australia

Qiao Wang

NICTA; Victoria Research Laboratory; Department of Computer Science and Software Engineering; The University of Melbourne; Melbourne, VIC Australia

Katrina Bell

Murdoch Childrens Research Institute; Royal Children’s Hospital; Parkville, VIC Australia

Elizabeth Algar

Murdoch Childrens Research Institute; Royal Children’s Hospital; Parkville, VIC Australia; Children’s Cancer Centre; Royal Children’s Hospital; Department of Paediatrics; University of Melbourne; Melbourne, VIC Australia

Jeffrey M Craig

Murdoch Childrens Research Institute; Department of Paediatrics; The University of Melbourne; Royal Children’s Hospital; Melbourne, VIC Australia

Richard Saffery

Murdoch Childrens Research Institute; Department of Paediatrics; The University of Melbourne; Royal Children’s Hospital; Melbourne, VIC Australia

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.

Received: January 26, 2012; Accepted: March 28, 2012

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