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||Immune Correlates and Mechanisms of Perinatal Cytomegalovirus Infection and Later Life All Development
Acute lymphoblastic leukemia (ALL), the most common malignancy of childhood, has a suspected prenatal origin
in a majority of cases. Although nearly 90% of ALL patients survive into adulthood, treatment has devastating
long-term health effects and primary prevention remains the quintessential goal of oncology research. Children
who develop ALL exhibit alterations in inflammatory cytokine levels at birth and experience more medically
diagnosed early-life infections, suggesting that early-life infections may be a modifiable etiologic agent. We
recently demonstrated that pretreatment bone marrow specimens from children with ALL had prevalent
cytomegalovirus (CMV) infection. Screening of archived newborn blood samples from 268 children who went on
to develop ALL and 270 cancer-free control children demonstrated that ALL patients were nearly 4-times more
likely to have detectable CMV in their blood at birth (OR=3.71, P=0.0016), suggesting that congenital CMV
infection is an ALL risk factor. CMV is the most common congenital infection worldwide, affecting 1 in 150 infants.
CMV infection prior to birth likely has a significant impact on the developing immune system, including T cell
activation and central tolerance. CMV has the largest genome of any human viral pathogen and harbors many
immune-evasion genes, indicating that CMV modulates the host immune system to escape immunosurveillance.
The mechanisms underlying this CMV-induced immune modulation are poorly understood; however, other
oncogenic viruses can induce widespread methylation changes to the host epigenome. Virally-induced
epigenetic changes may alter the transcriptional landscape of the developing immune system and negatively
impact both lineage commitment during hematopoiesis and host immunosurveillance, thereby augmenting ALL
risk. Thus, defining the interaction between congenital CMV infection and dysregulation of leukemia-associated
genes in early life is an important step toward establishing the mechanistic link between congenital CMV infection
and ALL risk, a potentially vaccine-preventable cancer risk factor. We hypothesize that congenital CMV infection
induces epigenetic and immunologic changes in the developing fetus that contribute to risk of developing ALL
during childhood. Using a matched case-control sample of CMV-infected, CMV-exposed, and CMV-unexposed
cord blood donors from the Carolinas Cord Blood Bank, we will identify the epigenetic and immunologic
consequences of congenital CMV infection. We will then determine if CMV infection-associated epigenetic and
immunologic changes are recapitulated in newborn blood spots from children who went on to develop ALL.
Finally, we will determine whether known ALL susceptibility variants modify risk of congenital CMV infection by
comparing the frequency of these variants in CMV-infected cord blood donors to uninfected controls. These
studies will elucidate the role of congenital CMV infection on later cancer risk and help to identify modifiable
early-life factors that can reduce the public health burden associated with the most common cancer of childhood.