title: History of Parvovirus B19 infection is associated with a DNA methylation signature in childhood acute lymphoblastic leukemia.
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.
authors.affiliation: Programa de Hematologia e Oncologia Pediátricas, Centro de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
authors.forename: Gisele M
authors.initials: GM
authors.lastname: Vasconcelos
authors.forename: Brock C
authors.initials: BC
authors.lastname: Christensen
authors.forename: E Andrés
authors.initials: EA
authors.lastname: Houseman
authors.forename: Jianqiao
authors.initials: J
authors.lastname: Xiao
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Marsit
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.forename: Shichun
authors.initials: S
authors.lastname: Zheng
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Karagas
authors.forename: Heather H
authors.initials: HH
authors.lastname: Nelson
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wrensch
authors.forename: Karl T
authors.initials: KT
authors.lastname: Kelsey
authors.forename: Maria S
authors.initials: MS
authors.lastname: Pombo-de-Oliveira
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Wiemels
mesh_terms: D000293:Adolescent; D001853:Bone Marrow / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010322:Parvoviridae Infections / Q000150:complications* / Q000276:immunology; D016732:Parvovirus B19, Human; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000276:immunology / Q000821:virology*; D011401:Promoter Regions, Genetic