[CANCER RESEARCH 61, 2542–2546, March 15, 2001] Transplacental Chemical Exposure and Risk of Infant Leukemia with MLL Gene Fusion 1 Freda E. Alexander, 2 Sherry L. Patheal, Andrea Biondi, Silvia Brandalise, Maria-Elena Cabrera, Li C. Chan, Zhu Chen, Giuseppe Cimino, Jose-Carlos Cordoba, Long-Jun Gu, Hany Hussein, Eiichi Ishii, Azza M. Kamel, Silvia Labra, Isis Q. Magalha ˜es, Shuki Mizutani, Eleni Petridou, Maria Pombo de Oliveira, Patrick Yuen, Joseph L. Wiemels, and Mel F. Greaves Department of Public Health Science, University of Edinburgh, Edinburgh EH8 9AG, United Kingdom [F. E. A., S. L. P.]; Clinica Pediatrica, Universita ` Milano, Ospedale S. Gerardo, 20052 Monza, Italy [A. B.]; Centro Infantil de Investigac ¸o ˜es Hematolo ´gicas D. Boldrini, Rua Dr. Gabriel Porto, 1270, Bara ˜o Geraldo, CEP 13 083 210 Campinas, Sau Paulo, Brazil [S. B.]; Haematology Section, University of Chile, Hospital del Salvador, Santiago, Chile [M-E. C., S. L.]; Department of Pathology, University of Hong Kong, Queen Mary Hospital Compound, Hong Kong [L. C. C.]; Shanghai Institution of Hematology, Shanghai Second Medical University, Shanghai, China [Z. C.]; Department of Cellular Biotechnology and Hematology, University ‘La Sapienza’ of Rome, Rome, Italy [G. C.]; Hospital de Apoio Brasilia, Unidade de Onco-Hematologia Pediatrica, SGAIN Q.4, CEP 72 620 000-Brasilia, Brazil [J-C. C., I. Q. M.]; Department of Pediatric Hematology/Oncology, Xinhua Hospital/Shanghai Children’s Medical Centre, Shanghai Second Medical University, Shanghai, China [L-J. G.]; Department of Pediatric Oncology, National Cancer Institute, Cairo University, Kasr El Eini St, Fum El-Khalig, Cairo, Egypt [H. H.]; Division of Pediatrics, Hamanomachi Hospital 3-5-27 Maizuru, Chuo-ku Fukuoka 810-8539, Japan [E. I.]; Department of Clinical Pathology, National Cancer Institute, Cairo University, Kasr El Eini St, Fum El-Khalig, Cairo, Egypt [A. M. K.]; Department of Pediatrics and Developmental Biology, Postgraduate Medical School, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan [S. M.]; Department of Hygiene and Epidemiology, University of Athens, School of Medicine, 11527 Athens, Greece [E. P.]; Instituto Nacional de Cancer, Praca Cruz Vermelha, 7o. andar, Laboratorio de Marcadores Celulares-Hematologia Clinica, CEP 20230-130, Rio de Janeiro, Brazil [M. P. d. O.]; Department of Paediatrics, The Chinese University, Hong Kong [P. Y.]; and Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, United Kingdom [J. L. W., M. F. G.] ABSTRACT Infant acute leukemia (IAL) frequently involves breakage and recom- bination 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 chem- icals 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 (includ- ing 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 dipy- rone, Baygon, and other carbamate-based insecticides in certain settings, confirmation of these apparent associations is urgently required. INTRODUCTION In most cases of IAL 3 , both ALL and AML have rearrangements of the MLL gene at 11q23, which are referred to as MLL +ve (1– 4). Investigation of identical twin pairs, concordant for infant leukemia (5), has shown that this genetic lesion was acquired in utero by one twin and transferred to the other, and in utero origin has been confirmed by retrospective analyses of neonatal blood spots (Guthrie cards) of affected infants (6). The high concordance rate for leukemia in monozygotic twins of this age and the very short latency suggests that an MLL fusion in the appropriate fetal hematopoietic stem cell is sufficient to cause leukemia (7). MLL rearrangements are rare in older cases of de novo leukemia but frequent in cases arising subsequent to chemotherapy with inhibitors of topo-II. This suggested that similar exposures in utero might be relevant to infant leukemia (5) and has led to the specific biologically based hypothesis that MLL +ve infant leukemia is caused by transplacental exposure to substances that form cleavable complexes with topo-II (8, 9). Although the hypothesis is very precise in terms of case biological subgroups, timing of exposure, and biological mechanism, it is diffi- cult to test because many inhibitors of topo-II remain unidentified. An additional problem is that the magnitude of the effect of different substances is unknown, so that computation of total exposure is not possible. topo-II inhibitors include chemotherapeutic agents (10), benzene metabolites (such as benzoquinone and, hence, smoking; Refs. 11, 12), isoflavones, flavonoids, lignans (e.g., Ref. 13), some herbal medicines (14), anthraquinone laxatives such as senna (15), podophyl- lin resin, quinolone antibiotics, some pesticides including certain fungicidals and mosquitocidals (16, 17), some culinary herbs (e.g., turmeric; Ref. 18), and many, though not all, phenolic substances or their metabolites (19). 4 Herbal medicines are frequently potent (20, 21), and an association with MLL +ve AIL was a prior hypothesis. Limited epidemiological support is available. Maternal dietary con- sumption of topo-II inhibitors has been associated specifically with infant acute myeloid leukemia in one United States case-control study (n = 84 cases; Ref. 22). The metabolism of quinones, as exemplified by benzene detoxification, is critically controlled by the enzyme NQ01 (19). Two polymorphic variants of NQ01 have been identified (23). The first effectively inactivates the enzyme (24). This has been associated with chemotherapy-related leukemia (25) and MLL +ve infant leukemia (26). The objectives of the present study were: (a) to test the hypothesis that exposure in utero known to inhibitors of topo-II increased risk of MLL +ve infant leukemia; (b) to conduct a preliminary evaluation of Received 4/24/00; accepted 1/24/01. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by the Kay Kendall Leukaemia Fund. Additional local funding came from the Associazione Italiana per la Lotta contro le Leucemie-Sezione di Roma (ROMAIL), the Japan Leukemia Research Fund, the Japan Children’s Cancer Association, a Grant-in Aid for Cancer Research from the Ministry of Health and Welfare of Japan, the University of Athens Medical School, and the Harvard School of Public Health. The support of The Hong Kong Paediatric and Haematology Study Group, the Japan Infant Leukemia Study Group, and the Hematology and Oncology Group of Greece is acknowledged. 2 To whom requests for reprints should be addressed, at Department of Public Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, United Kingdom. 3 The abbreviations used are: IAL, infant acute leukemia; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; topo-II, topoisomerase II; NQ01, NADPH: quinone oxidoreductase; OR, odds ratio; CI, confidence interval. 4 M. Smith, personal communication. 2542 Research. on June 25, 2015. © 2001 American Association for Cancer cancerres.aacrjournals.org Downloaded from