In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia

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

doi:10.1182/blood-2016-07-723148

Cited by 67 publications

(88 citation statements)

References 23 publications

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“…Risk classification at the moment of diagnosis was based on the National Cancer Institute [31] risk criteria. Patients between 1 and 10 years old and a leukocyte count <50 x 109/L were classified as NCI standard-risk whereas those aged �10 years or a leukocyte count �50 x 109/ L were classified as NCI high-risk.…”

Section: Clinical Data Collection and Risk Classificationmentioning

confidence: 99%

Functional characterization of NK cells in Mexican pediatric patients with acute lymphoblastic leukemia: Report from the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia

et al. 2020

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Section: Clinical Data Collection and Risk Classificationmentioning

confidence: 99%

Functional characterization of NK cells in Mexican pediatric patients with acute lymphoblastic leukemia: Report from the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia

et al. 2020

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“…Infections early in life have long been suspected to play a role in the development of childhood acute lymphoblastic leukemia (ALL), in particular B-cell precursor ALL, the most common subtype. Many B-cell precursor ALL cases (e.g., high-hyperdiploidy and ETV6-RUNX1-translocated cases) are initiated in utero (1)(2)(3), and exposure to infections during pregnancy may increase offspring's risk of this intrauterine preleukemic development (4)(5)(6)(7). Furthermore, it has been suggested that a lack of exposure to infections in early childhood can cause an abnormal immune response to infections later in childhood, leading to the transformation of preleukemic cells to leukemia.…”

Section: Introductionmentioning

confidence: 99%

Neonatal Inflammatory Markers Are Associated with Childhood B-cell Precursor Acute Lymphoblastic Leukemia

et al. 2018

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It has been proposed that children with acute lymphoblastic leukemia (ALL) are born with a dysregulated immune function that together with postnatal environmental exposures causes childhood ALL. Despite its importance for the understanding of ALL etiology, this hypothesis has been inadequately explored. In a population-based case-control study, we measured the concentrations of 10 cytokines and other inflammatory markers on neonatal dried blood spots from 178 children who at ages 1 to 9 years were diagnosed with B-cell precursor ALL and 178 matched controls. Through linkage with Danish nationwide registers, we also assessed whether neonatal inflammatory markers were associated with previously demonstrated risk factors for childhood ALL. Children who developed B-cell precursor ALL had significantly lower neonatal concentrations of IL8, soluble IL6 receptor (sIL6R) α, TGFβ1, monocyte chemotactic protein (MCP)-1, and C-reactive protein (CRP) and higher concentrations of IL6, IL17, and IL18 compared with matched controls. Concentrations of IL10 were below the detection level for both patients and controls. Birth order (IL18 and CRP), gestational age (sIL6Rα, TGFβ1, and CRP), and sex (sIL6Rα, IL8, and CRP), but not maternal age, infections during pregnancy, birth weight nor mode of delivery were significantly associated with the neonatal concentrations of inflammatory markers. Our findings support the hypothesis that children who later develop B-cell precursor ALL are born with a dysregulated immune function. Children who develop acute lymphoblastic leukemia are immunologically distinct at birth and could potentially react abnormally to infections in early childhood. .

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“…The clinical signs of CMV congenital infection include thrombocytopenia and anemia . Our study did not specifically assess the capacity of hematopoietic progenitors to form megakaryocytic CFUs; however, the circulating platelet counts were not significantly different between CB donors with CMV infection and the control group.…”

Section: Discussionmentioning

confidence: 74%

Cytomegalovirus viral load in cord blood and impact of congenital infection on markers of hematopoietic progenitor cell potency

et al. 2017

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BACKGROUND The low incidence of cytomegalovirus (CMV) infection in neonates decreases the risk of viral transmission with cord blood transplantation. Cord blood donors are screened by testing the maternal sample for total antibodies to CMV. Some cord blood banks also screen cord blood for CMV‐DNA. The aim of this study was to develop and validate a multiplex real‐time polymerase chain reaction assay to measure CMV viral load in cord blood from asymptomatic infants with congenital CMV infection and to assess the impact of CMV infection on cord blood hematopoietic progenitor cell concentrations and colony‐forming unit functionality. STUDY DESIGN AND METHODS CMV infection was evaluated in two groups of cord blood donors: 1) 30,308 neonates prospectively screened by saliva culture, including 41 positive cases (0.14%), all from mothers with total antibodies to CMV; and 2) 4712 newborns from mothers with total antibodies to CMV who were screened retrospectively by polymerase chain reaction, including 18 positive cases (0.38%). All 59 infants with CMV were asymptomatic at birth. RESULTS Among the 59 positive cases, the average CMV viral load in cord blood was 20.6 × 104 viral copies (vc)/mL; seven of 59 mothers (12%) had CMV‐DNA detected, however, with no association to their newborns' CMV viral load. Levels of colony‐forming units, CD34+/CD45+ cells, and total nucleated cells measured in a cohort of CMV‐positive cord blood samples were higher than those in the matched control group. CONCLUSION We developed and validated a multiplex real‐time polymerase chain reaction assay to detect CMV‐DNA in cord blood. In our study, maternal total antibodies to CMV or CMV‐DNA at birth were poor predictors of infection in cord blood donors. Furthermore, our results suggest that CMV congenital infection impacts CD34+/CD45+ cells and some hematopoietic progenitor cells toward higher proliferation.

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In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia

Abstract: Key Points CMV is prevalent in pretreatment bone marrow from childhood ALL and not in acute myeloid leukemia. In utero infection with CMV is a risk factor for ALL (OR = 3.71, P = .0016) and is more pronounced in Hispanics (OR = 5.90, P = .006).

Cited by 67 publications

References 23 publications

Functional characterization of NK cells in Mexican pediatric patients with acute lymphoblastic leukemia: Report from the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia

Functional characterization of NK cells in Mexican pediatric patients with acute lymphoblastic leukemia: Report from the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia

Neonatal Inflammatory Markers Are Associated with Childhood B-cell Precursor Acute Lymphoblastic Leukemia

Cytomegalovirus viral load in cord blood and impact of congenital infection on markers of hematopoietic progenitor cell potency

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