Grant Number:	1R21CA242439-01 Interpret this number
Primary Investigator:	Walsh, Kyle
Organization:	Duke University
Project Title:	Immune Correlates and Mechanisms of Perinatal Cytomegalovirus Infection and Later Life All Development
Fiscal Year:	2019

ABSTRACT 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.




In utero human cytomegalovirus infection expands NK-like FcγRIII+CD8+ T cells that mediate Fc antibody functions.
Authors: Semmes E.C. , Nettere D.R. , Nelson A.N. , Hurst J.H. , Cain D.W. , Burt T.D. , Kurtzberg J. , Reeves R.K. , Coyne C.B. , Fouda G.G. , et al. .
Source: The Journal Of Clinical Investigation, 2024-11-12 00:00:00.0; 135(1), .
EPub date: 2024-11-12 00:00:00.0.
PMID: 39531313
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Maternal Prenatal Use of Alcohol, Tobacco, and Illicit Drugs and Associations with Childhood Cancer Subtypes.
Authors: Wimberly C.E. , Gulrajani N.B. , Russ J.B. , Landi D. , Wiemels J.L. , Towry L. , Wiencke J.K. , Walsh K.M. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2024-03-01 00:00:00.0; 33(3), p. 347-354.
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ADCC-activating antibodies correlate with decreased risk of congenital human cytomegalovirus transmission.
Authors: Semmes E.C. , Miller I.G. , Rodgers N. , Phan C.T. , Hurst J.H. , Walsh K.M. , Stanton R.J. , Pollara J. , Permar S.R. .
Source: Jci Insight, 2023-07-10 00:00:00.0; 8(13), .
EPub date: 2023-07-10 00:00:00.0.
PMID: 37427588
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Does congenital cytomegalovirus infection contribute to the development of acute lymphoblastic leukemia in children?
Authors: Toor R.K. , Semmes E.C. , Walsh K.M. , Permar S.R. , Giulino-Roth L. .
Source: Current Opinion In Virology, 2023 Jun; 60, p. 101325.
EPub date: 2023-04-17 00:00:00.0.
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Beyond Anxiety and Grief: Mapping the Emotional Landscape of Parents Facing a Childhood Cancer Diagnosis.
Authors: Sheikh S. , Wimberly C.E. , Towry L. , Walsh K.M. .
Source: Medrxiv : The Preprint Server For Health Sciences, 2023-05-28 00:00:00.0; , .
EPub date: 2023-05-28 00:00:00.0.
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Maternal Fc-mediated non-neutralizing antibody responses correlate with protection against congenital human cytomegalovirus infection.
Authors: Semmes E.C. , Miller I.G. , Wimberly C.E. , Phan C.T. , Jenks J.A. , Harnois M.J. , Berendam S.J. , Webster H. , Hurst J.H. , Kurtzberg J. , et al. .
Source: The Journal Of Clinical Investigation, 2022-08-15 00:00:00.0; 132(16), .
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Congenital Human Cytomegalovirus Infection Is Associated With Decreased Transplacental IgG Transfer Efficiency Due to Maternal Hypergammaglobulinemia.
Authors: Semmes E.C. , Li S.H. , Hurst J.H. , Yang Z. , Niedzwiecki D. , Fouda G.G. , Kurtzberg J. , Walsh K.M. , Permar S.R. .
Source: Clinical Infectious Diseases : An Official Publication Of The Infectious Diseases Society Of America, 2022-04-09 00:00:00.0; 74(7), p. 1131-1140.
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SARS-CoV-2 vaccine acceptability among caregivers of childhood cancer survivors.
Authors: Wimberly C.E. , Towry L. , Davis E. , Johnston E.E. , Walsh K.M. .
Source: Pediatric Blood & Cancer, 2021-11-17 00:00:00.0; , p. e29443.
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Impacts of COVID-19 on caregivers of childhood cancer survivors.
Authors: Wimberly C.E. , Towry L. , Caudill C. , Johnston E.E. , Walsh K.M. .
Source: Pediatric Blood & Cancer, 2021-02-09 00:00:00.0; , p. e28943.
EPub date: 2021-02-09 00:00:00.0.
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Cytomegalovirus as an immunomodulator across the lifespan.
Authors: Semmes E.C. , Hurst J.H. , Walsh K.M. , Permar S.R. .
Source: Current Opinion In Virology, 2020-08-17 00:00:00.0; 44, p. 112-120.
EPub date: 2020-08-17 00:00:00.0.
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Leveraging genome and phenome-wide association studies to investigate genetic risk of acute lymphoblastic leukemia.
Authors: Semmes E.C. , Vijayakrishnan J. , Zhang C. , Hurst J.H. , Houlston R.S. , Walsh K.M. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2020-05-28 00:00:00.0; , .
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