Transplacental chemical exposure and risk of infant leukemia with MLL gene fusion

Infant acute leukemia (IAL) frequently involves breakage and recombination of the MLL gene with one of several potential partner genes. These gene fusions arise in utero and are similar to those found in leukemias secondary to chemotherapy with inhibitors of topoisomerase II (topo-II). This has led...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2001-03, Vol.61 (6), p.2542-2546
Main Authors: ALEXANDER, Freda E, PATHEAL, Sherry L, HUSSEIN, Hany, ISHII, Eiichi, KAMEL, Azza M, LABRA, Silvia, MAGALHAES, Isis Q, MIZUTANI, Shuki, PETRIDOU, Eleni, POMBO DE OLIVEIRA, Maria, YUEN, Patrick, WIEMELS, Joseph L, BIONDI, Andrea, GREAVES, Mel F, BRANDALISE, Silvia, CABRERA, Maria-Elena, CHAN, Li C, ZHU CHEN, CIMINO, Giuseppe, CORDOBA, Jose-Carlos, GU, Long-Jun
Format: Article
Language:English
Subjects:
Acute Disease
Artificial Gene Fusion
Biological and medical sciences
Case-Control Studies
dipyrone
DNA-Binding Proteins - genetics
Enzyme Inhibitors - adverse effects
Enzyme Inhibitors - pharmacokinetics
Female
Hematologic and hematopoietic diseases
Histone-Lysine N-Methyltransferase
Humans
Infant
Infant acute leukemia
Infant, Newborn
Leukemia, Myeloid - chemically induced
Leukemia, Myeloid - genetics
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Male
Maternal-Fetal Exchange
Medical sciences
MLL gene
Myeloid-Lymphoid Leukemia Protein
Pilot Projects
Precursor Cell Lymphoblastic Leukemia-Lymphoma - chemically induced
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Pregnancy
Prenatal Exposure Delayed Effects
Proto-Oncogenes
Risk Factors
Topoisomerase II Inhibitors
Transcription Factors
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Summary:Infant acute leukemia (IAL) frequently involves breakage and recombination of the MLL gene with one of several potential partner genes. These gene fusions arise in utero and are similar to those found in leukemias secondary to chemotherapy with inhibitors of topoisomerase II (topo-II). This has led to the hypothesis that in utero exposures to chemicals may cause IAL via an effect on topo-II. We report a pilot case-control study of IAL across different countries and ethnic groups. Cases (n = 136) were population-based in most centers. Controls (n = 266) were selected from inpatients and outpatients at hospitals serving the same populations. MLL rearrangement status was derived by Southern blot analysis, and maternal exposure data were obtained by interviews using a structured questionnaire. Apart from the use of cigarettes and alcohol, very few mothers reported exposure to known topo-II inhibitors. Significant case-control differences were apparent for ingestion of several groups of drugs, including herbal medicines and drugs classified as "DNA-damaging," and for exposure to pesticides with the last two being largely attributable, respectively, to one nonsteroidal anti-inflammatory drug, dipyrone, and mosquitocidals (including Baygon). Elevated odds ratios were observed for MLL+ve (but not MLL-ve) leukemias (2.31 for DNA-damaging drugs, P = 0.03; 5.84 for dipyrone, P = 0.001; and 9.68 for mosquitocidals, P = 0.003). Although it is unclear at present whether these particular exposures operate via an effect on topo-II, the data suggest that specific chemical exposures of the fetus during pregnancy may cause MLL gene fusions. Given the widespread use of dipyrone, Baygon, and other carbamate-based insecticides in certain settings, confirmation of these apparent associations is urgently required.
ISSN:0008-5472
1538-7445