Perinatal Immune Development and Risk of Childhood Acute Lymphoblastic Leukemia

Investigator: Joseph Wiemels, PhD
Sponsor: NIH National Cancer Institute

Location(s): United States


Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children (age 0-14 years), but the causes of the disease are largely unknown. In this research project, we will study 500 children with ALL, 500 children without ALL, and the mothers of the 1000 children to assess whether mother's immune status during pregnancy and the genetic characteristics of the mother and her child affect the child's immune status at birth and the risk of developing ALL later in life (up until 14 years of age). Results of this study will help us better understand how immune development might be related to childhood ALL.

Childhood leukemia is the most common childhood cancer but the causes of the disease are uncertain in the vast majority of cases. Epidemiology studies have pointed to patterns of infection being influential risk factors for leukemia - with exposure to a wide variety and number of childhood contacts (e.g., daycare and older siblings) being protective for leukemia. These associations are strongest for the pre-B cell immunophenotype of leukemia, which we will study here. New epidemiologic evidence suggests that vigorous response to infections, meaning infections that require care from medical professionals, is a risk factor for leukemia. Additionally, children who contract leukemia have a deficit of the immunosuppressive cytokine IL10 at birth when compared to control children who did not get leukemia, meaning that they enter the world with a congenital immune aberration. We hypothesize, based on these observations, that features of neonatal immune function, namely a lack of immunosuppression, are important in risk of pre-B cell acute lymphoblastic leukemia (pre-B ALL). In the current study we will further define this immunosuppressive phenotype in more detail and examine the developmental fetal genetic interaction and maternal environmental factors that influence this fetal phenotype. We will assemble a series of 500 ALL case children and their mothers, and 500 controls with their mothers to assess whether two genetic factors (HLA-C and KIR) critical in developing a supportive immune environment for a fetus within its mother can influence fetal immune status and leukemia case/control status. We will additionally assess, with 200 case mothers and 500 control mothers, whether neonatal immune function phenotype is influenced by maternal immune status during pregnancy. We will define fetal immune phenotype by additional markers besides only IL10 levels, including TGF-¿, IFN-¿, and T- regulatory cell marker - a differentially-methylated region of the critical transcription factor FOXP3. The impact of maternal cytokines and IGE levels, and KIR genotypes (along with HLA-C genotypes in the neonate) will first be assessed on neonatal immune function among controls. Both maternal and fetal immune phenotypes will then be assessed for their impact in prediction of case status. The results of this study will further defie critical characteristics in immune development that influence a cancer of the immune system. These results will benefit efforts to understand the etiology of leukemia as well aid predictive and preventative modalities for childhood leukemia, and set the stage for follow-up studies that examine postnatal factors that combine together with congenital immune immunosuppression to produce leukemia.