Superfund Research Program
Multidisciplinary Studies of the Origins of Childhood Leukemia
The study of childhood leukemia is important because leukemia is the number one cause of cancer morbidity and mortality in children in the United States. The causes for 90% of childhood leukemias are unknown and the environmental and genetic contributions to this disease are not well characterized. As part of the Northern California Childhood Leukemia Study (NCCLS), Drs. Patricia Buffler and Martyn Smith at the University of California-Berkeley and Dr. Joseph Wiemels at the University of California-San Francisco have conducted research examining two critical aspects of the origins of childhood leukemia.
As part of ongoing SBRP-funded research, scientists led by Drs. Smith and Wiemels are using a sophisticated molecular technology to help unravel the origins of the mutations that lead to some childhood leukemias. Leukemia may arise following the abnormal fusion of two genes, which results in production of abnormal proteins. The research team studied leukemias stemming from the fusion of genes known as AML1 and ETO. This fusion, referred to as t(8;21)AML1-ETO translocation, is present in a type of childhood acute myeloid leukemia (AML), the most difficult type of leukemia to treat. The AML1 protein is a "master" regulator of gene activity for blood cell development from stem cells. If the AML1-ETO fusion occurs in just one out of the thousands of stem cells a person is born with, then the stage is set for a second gene mutation to trigger the leukemia, even if the second mutation occurs years later.
The research team examined both diagnostic blood samples and neonatal "heel prick" blood spots from children with AML, two of whom were older than 10 years of age at diagnosis. The scientists detected t(8;21)AML1-ETO in the "heel prick" blood samples for 5 individuals, showing that the translocation must have occurred in utero, providing unambiguous evidence of prenatal origin in these cases and suggesting that exposures of the fetus before birth could be critical in producing childhood leukemia.
The discovery of this "latency period" between the initiating genetic event and full development of leukemia suggests that even some adult leukemia may start in the womb. These results further implicate the fetal period as a distinctly susceptible period for chromosomal translocation, perhaps the usual period for such events among pediatric leukemias.
In addition to the current report of the in utero t(8;21)AML1-ETO translocation in leukemia patients, the research team has confirmed that two other mutations, the MLL and TEL-AML1 translocations, have prenatal origins. Childhood cancers besides leukemia, particularly sarcomas, are commonly associated with translocations. The t(8;21)AML1-ETO translocation biomarker has particular significance in that it is not merely associated with acute myeloid leukemia, but is on the causal pathway of the environmentally-induced cancer and as a result should be a better predictor of increased cancer risk than existing biomarkers.
By studying the similarities in the pregnancies that harbored the initial genetic mutation in this type of leukemia, the SBRP-funded scientists hope to identify the dietary, environmental or other causes for the potentially harmful mutation. As part of the NCCLS, Dr. Buffler and colleagues examined 162 children newly diagnosed with childhood leukemia (age 0-14 years) and 162 matched control subjects randomly selected from the birth registry. Cases and controls were similar with respect to age, gender, race, Hispanicity, maternal education, and maternal age.
This study is unique in that it focuses on residential exposure rather than parental occupational exposure. The research team conducted in-home personal interviews with the primary care givers to collect detailed information on household pesticide usage including the name of each product; intended purpose (such as cockroach control); frequency of use; and time windows of use - 3 months prior to pregnancy, pregnancy, and the first, second, and third years of life.
The results of this study:
- Provide strong support of previous observations that indicating that exposure to household pesticides is associated with an increased risk of childhood leukemia.
- Indicate that insecticide exposures early in life appear to be more significant than later exposures, with the highest risk observed for exposure during pregnancy.
- Distinguish between the risks associated with different types of pest control, demonstrating a dose response relationship, and indicating the importance of the timing and location of exposure.
- Show a significant association between the use of professional pest control services and an increased risk of childhood leukemia. The magnitude of this association was larger than what was seen for general insecticide or indoor pesticide exposures.
This information may enable us to educate the public concerning possible risks associated with exposures to pesticides, with particular emphasis on the timing and location of exposure.
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To learn more about this research, please refer to the following sources:
- Ma X, Buffler PA, Gunier RB, Dahl GV, Smith MT, Reinier K, Reynolds P. 2002. Critical windows of exposure to household pesticides and risk of childhood leukemia. Environ Health Perspect 110(9):955-960. PMID:12204832
- Wiemels JL, Xiao Z, Buffler PA, Maia AT, Ma X, Dicks BM, Smith MT, Zhang L, Feusner J, Wiencke JK, Pritchard-Jones K, Kempski H, Greaves MF. 2002. In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia. Blood 99(10):3801-3805. PMID:11986239
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