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In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia

Stephen Starko Francis, Amelia D. Wallace, George A. Wendt, Linlin Li, Fenyong Liu, Lee W. Riley, Scott Kogan, Kyle M. Walsh, Adam J. de Smith, Gary V. Dahl, Xiaomei Ma, Eric Delwart, Catherine Metayer and Joseph L. Wiemels

Key points

  • Cytomegalovirus (CMV) is prevalent in pre-diagnostic bone marrow from childhood ALL and not in AML.

  • In utero infection with CMV is a risk factor for ALL (OR=3.71, p=0.0016) and is more pronounced in Hispanics (OR=5.90, p=0.006).

Abstract

It is widely suspected, yet controversial, that infection plays an etiologic role in the development of acute lymphoblastic leukemia (ALL), the most common childhood cancer and a disease with a confirmed prenatal origin in most cases. We investigated infections at diagnosis and then assessed the timing of infection at birth in children with ALL and age, gender, and ethnicity matched controls to identify potential causal initiating infections. Comprehensive untargeted virome and bacterial analyses of pre-treatment bone marrow specimens (n=127 ALL compared to 38 acute myeloid leukemia cases as comparison group) revealed prevalent cytomegalovirus (CMV) infection at diagnosis in childhood ALL, demonstrating active viral transcription in leukemia blasts as well as intact virions in serum. Screening of newborn blood samples revealed a significantly higher prevalence of in utero CMV infection in ALL cases (n=268) than healthy controls (n=270) (OR=3.71, CI=1.56-7.92, p=0.0016). Risk was more pronounced in Hispanics (OR=5.90, CI=1.89-25.96) vs. non-Hispanic whites (OR=2.10 CI= 0.69-7.13). This is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children. Further investigation of CMV as an etiologic agent for ALL is warranted.

  • Submitted July 5, 2016.
  • Accepted September 17, 2016.