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Authors: Gisele M. Vasconcelos, Brock C. Christensen, E. Andrés Houseman, Jianqiao Xiao, Carmen J. Marsit, John K. Wiencke, Shichun Zheng, Margaret R. Karagas, Heather H. Nelson, Margaret R. Wrensch, Karl T. Kelsey, Maria S. Pombo-de-Oliveira and Joseph L. Wiemels

Gisele M. Vasconcelos

Programa de Hematologia e Oncologia Pediátricas, Centro de Pesquisa, Instituto Nacional de Câncer; Rio de Janeiro, Brazil; and Laboratory for Molecular Epidemiology, Department of Epidemiology and Biostatistics; University of California in San Francisco; San Francisc, CA USA

Brock C. Christensen

Department of Community Health, Center for Environmental Health and Technology; Brown University; Providence, RI USA; and Department of Pathology and Laboratory Medicine; Brown University; Providence, RI USA

E. Andrés Houseman

College of Public Health and Human Sciences; Corvallis, OR USA

Jianqiao Xiao

Laboratory for Molecular Epidemiology, Department of Epidemiology and Biostatistics; University of California in San Francisco; San Francisc, CA USA

Carmen J. Marsit

Department of Community Health, Center for Environmental Health and Technology; Brown University; Providence, RI USA; and Department of Pathology and Laboratory Medicine; Brown University; Providence, RI USA

John K. Wiencke

Department of Neurosurgery, University of California San Francisco; San Francisco, CA USA

Shichun Zheng

Department of Neurosurgery, University of California San Francisco; San Francisco, CA USA

Margaret R. Karagas

Section of Biostatistics and Epidemiology, Department of Community and Family Medicine; Dartmouth Medical School; Lebanon, NH USA

Heather H. Nelson

Margaret R. Wrensch

Karl T. Kelsey

Maria S. Pombo-de-Oliveira

Corresponding author: mpombo@inca.gov.br

Joseph L. Wiemels

Corresponding author: joe.wiemels@ucsf.edu

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Abstract:

Acute lymphoblastic leukemia (ALL) likely has a multistep etiology, with initial genetic aberrations occurring early in life. An abnormal immune response to common infections has emerged as a plausible candidate for triggering the proliferation of pre-leukemic clones and the fixation of secondary genetic mutations and epigenetic alterations. We investigated whether evidence of infection with a specific common myelotropic childhood virus, parvovirus B19 (PVB19), relates to patterns of gene promoter DNA methylation in ALL patients. We serologically tested bone marrow samples at diagnosis of B-cell ALL for PVB19 infection and DNA methylation using a high-throughput bead array and found that 4.2% and 36.7% of samples were seroreactive to PVB19 IgM and IgG, respectively. Leukemia samples were grouped by DNA methylation pattern. Controlling for age and immunophenotype, unsupervised modeling confirmed that the DNA methylation pattern was associated with history of PVB19 (assessed by IgG, p = 0.02), but not recent infection (assessed by IgM). Replication assays on single genes were consistent with the association. The data indicate that a common viral illness may drive specific DNA methylation patterns in susceptible B-precursor cells, contributing to the leukemogenic potential of such cells. Infections may impact childhood leukemia by altering DNA methylation patterns and specific key genes in susceptible cells; these changes may be retained even after the clearance of infection.