© The Author 2008. Published by Oxford University Press.
Environmental and Genetic Susceptibility to MLL-Defined Infant Leukemia
Affiliation of author: Division of Pediatric Epidemiology & Clinical Research, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Correspondence to: Julie A. Ross, PhD, Division of Pediatric Epidemiology & Clinical Research, Department of Pediatrics, University of Minnesota Cancer Center, MMC 422, 420 Delaware St. S.E., Minneapolis, MN 55455 (e-mail: ross{at}umn.edu).
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ABSTRACT |
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 Top Abstract IntroductionClinical CharacteristicsGenetic CharacteristicsInfant Leukemia, DNA...Future DirectionsFundingReferences |
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The study of rare cancers, including retinoblastoma, angiosarcoma, and vaginal clear cell carcinoma, has contributed greatly to our understanding of cancer mechanisms. Infants with leukemia may represent another important rare group. The majority of infants with leukemia have MLL gene rearrangements in their leukemia cells, and there is unequivocal laboratory evidence that these arise in utero. There is increasing evidence that environmental and genetic factors may contribute to the risk of MLL-defined infant leukemias. Because the infant exposure experience is only a small window in comparison to that of an individual who develops a malignancy in middle or late age, the pivotal factors responsible for this genetic anomaly may be easier to identify. With the largest case–control study of infant leukemia ever conducted underway in the Children's Oncology Group (COG AE24), there is a unique opportunity to integrate epidemiological data with laboratory data on MLL status and genotype.
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INTRODUCTION |
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TopAbstractIntroductionClinical CharacteristicsGenetic CharacteristicsInfant Leukemia, DNA...Future DirectionsFundingReferences |
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Leukemia, the most common pediatric malignancy in the United States, accounting for approximately 33% of all new cancer diagnoses under the age of 15 years (1). For infants less than 12 months of age, leukemias comprise approximately 16% of all malignancies (second to neuroblastoma) with an overall incidence rate of about 36 cases per million infants. Given the molecular evidence that infant leukemia occurs in utero (2,3), epidemiologists have a promising opportunity to evaluate its potential causes. Some clinical and genetic characteristics of infant leukemia are provided below along with a discussion of future research directions.
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Clinical Characteristics |
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TopAbstractIntroductionClinical CharacteristicsGenetic CharacteristicsInfant Leukemia, DNA...Future DirectionsFundingReferences |
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Besides their young age, infants with leukemia are distinguished from older children with leukemia by morphological, immunological, and clinical presentation. For leukemias diagnosed in children less than 15 years of age, the percentage of acute lymphoblastic leukemia (ALL) cases is about four times that of acute myeloid leukemia (AML) (4). In contrast, the ratio of ALL to AML in infancy is reported to be between 1 and 1.5. Infant ALL typically presents with a very early pre–B cell phenotype, sometimes with myeloid antigen markers. Infant AML typically presents with an M4 or M5 morphology (5). The clinical features of infant acute leukemia are quite striking; often, there is a high blast count, organomegaly, and central nervous system involvement (6). Although considerable advances have been made in the treatment of childhood leukemia over the last 50 years, particularly for ALL, infants still fare poorly. The 5-year relative survival rate for children under the age of 15 years diagnosed with ALL is now approaching 80%, but for infants is less than 50% (1,7,8). For infant AML, the 5-year survival rates are around 40%, similar to what is reported for childhood AML overall. Importantly, there are frequent genetic abnormalities in infant leukemias that are also associated with clinical outcomes.
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Genetic Characteristics |
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TopAbstractIntroductionClinical CharacteristicsGenetic CharacteristicsInfant Leukemia, DNA...Future DirectionsFundingReferences |
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Infant leukemias (both AML and ALL) are associated more often with abnormalities (typically rearrangements) involving the MLL gene at chromosome 11 band q23 than any other region (9); these abnormalities are infrequently seen in older patients. The MLL gene, which has homology to a fruit fly homeobox gene, appears to play an important role in hematopoiesis (10,11). Numerous partner chromosomes have been involved in these MLL rearrangements, but the most common include chromosome 4, 6, 9, or 19. With improved technology for molecular detection, it is estimated that nearly 60% of infant AMLs and 75%–80% of infant ALLs have an MLL abnormality (ie, MLL+) in their leukemia cells (12,13). Possession of an MLL gene rearrangement is associated with clinical outcome for infant ALL [33.6% 5-year event free survival for MLL+ cases vs 60.3% for MLL– cases (8)] but not for infant AML (9). Interestingly, MLL rearrangements have also been observed in therapy-related leukemias (most often AMLs) involving the epipodophyllotoxins, including etoposide and teniposide (14,15); secondary ALL can also occur but to a much lesser extent (16). These therapies inhibit DNA topoisomerase II, an enzyme found in rapidly dividing cells that is responsible for the unwinding and religation of DNA (17).
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Infant Leukemia, DNA Topoisomerase II Inhibitors, and the MLL Gene |
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TopAbstractIntroductionClinical CharacteristicsGenetic CharacteristicsInfant Leukemia, DNA...Future DirectionsFundingReferences |
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Given the evidence that infant leukemia occurs in utero, we speculated over 10 years ago that "maternal" exposure to DNA topoisomerase II inhibitors during pregnancy may be associated with etiology (18). Several DNA topoisomerase II inhibitors exist, including those found in specific medications, chemicals, and foods (19–23) (see Table 1). We explored the hypothesis that maternal exposure to dietary DNA topoisomerase II inhibitors may increase risk of infant leukemia, and so we conducted a preliminary study that involved recontacting mothers of infants who previously participated in one of three Children's Cancer Group case–control studies of childhood leukemia (22). A combined dietary index of DNA topoisomerase II inhibitor–containing foods was created that evaluated low, medium, and high exposure. There was no positive association with either the overall group (n = 84 cases) or the ALL stratum (n = 54 cases). However, there was a statistically significant positive association within the AML stratum (n = 30 cases) such that the odds ratios (albeit very imprecise) were 9.8 (95% confidence interval [CI] = 1.1–84.8) and 10.2 (95% CI = 1.1–96.4) for medium and high exposure, respectively. We are currently conducting a case–control study of infant leukemia in the Children's Oncology Group and have published initial findings regarding this hypothesis (24). A total of 240 case mothers and 255 control mothers have been interviewed thus far. Unlike the older study, data regarding presence or absence of an MLL gene rearrangement were available for most (80%) cases. As shown in Figure 1, there was little evidence of an association between the DNA topoisomerase II inhibitor index and cases that were ALL/MLL+, ALL/MLL–, or AML/MLL–. However, there was an increasing linear trend (P = .10) with increasing maternal consumption of foods that inhibited DNA topoisomerase II among the AML/MLL+ cases. We consider these results preliminary, but intriguing. Case–control studies are often difficult to interpret due to concerns of recall bias, but it is unlikely that mothers of children with AML would recall selectively their dietary habits differently than mothers of children with ALL. Importantly, these results have raised several issues, some of which have been addressed previously (25).
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1) Bioavailability of Dietary Constituents to the Fetus
Several recent human feeding studies have demonstrated elevated plasma levels of flavonoids following consumption of specific foods [reviewed in (26)]. Interestingly, the bioavailability of certain constituents may depend on the food consumed; in one feeding study, the bioavailability of quercetin from apples was only 30% compared to onions (27). Adlercruetz and colleagues (28) studied seven Japanese women at delivery and measured six phytoestrogen metabolites (including genistein) in both maternal and cord blood; the concentrations were quite similar from both sources, suggesting that these compounds freely pass the placental barrier. Todaka et al. (29) recently found "higher" levels of certain phytoestrogens in cord serum compared to maternal serum, suggesting that certain compounds may remain longer in the fetus than in the mother.
2) Differences Between ALL and AML in Infants
DNA topoisomerase II inhibitor therapy-related leukemias are predominantly AML, with ALL being rarely observed (16), suggesting that the mechanism to reach infant ALL with an MLL abnormality may be different than that for AML. Genetic array studies show that ALLs that carry a translocation involving MLL possess a highly uniform and distinct pattern of gene expression that distinguishes them from ALLs without MLL rearrangements and AMLs (30). Thus, it seems important to explore where there are distinct etiological pathways for MLL+ ALL vs AML.
3) Ability of Dietary and Other Environmental Constituents to Directly Target the MLL Gene
Strick et al. (31) demonstrated that several dietary bioflavonoids can induce cleavage of the MLL gene in cell lines, as well as in myeloid and lymphoid progenitors (31). Sites of cleavage associated with bioflavonoids co-localized with the sites of cleavage of the MLL gene associated with etoposide. These data provide the most convincing laboratory evidence to date that flavonoids may be directly involved in causing damage at the MLL locus. A recent case–case analysis of 85 infants with leukemia explored associations with DNA topoisomerase II inhibitors and several DNA-damaging agents including dipryone (a nonsteroidal anti-inflammatory drug), metronidazole, and various pesticides and mosquitocidals; diet was not evaluated (32). There were statistically significant elevated risks associated with maternal use of a pesticide, as well as ingestion of dipyrone, with MLL+ infant leukemias only; no associations were found with the MLL– group. These results, along with our recent data above, provide further evidence that certain chemicals may directly target the MLL gene.
4) Rarity of Infant Leukemia
If these exposures are so common, why is infant leukemia so rare? The first answer may lie in the timing of exposure. For example, the critical time point for neural tube development is the third week of life, and it has been shown that periconceptional folic acid supplementation reduces risk of neural tube defects (33). It is possible that for infant leukemia the critical time point for exposure may be in the first few months of life when the site of hematopoiesis shifts from the yolk sac to the liver (34). Because it is difficult to obtain exposure information accurately in retrospective studies, perhaps animal models can help address this question. Secondly, there is growing evidence that polymorphisms in genes involved in the metabolism and detoxification of certain chemicals are important in etiology. For example, the low-activity variant of the NAD(p)H:quinone oxidoreductase (NQ01) gene, an enzyme that detoxifies quinones, appears overrepresented among infant leukemias with MLL gene rearrangements (35,36). Another study found a statistically significant reduced frequency of the low-function variant of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (C677T) in ALL/MLL+ infants compared to cord blood controls (37). Mother's genotype may also be important in determining which specific agents reach the fetus (38), although this has not been explored in infant leukemia. Taken together, infant and maternal genotypes, in combination with exposure (and the timing of the exposure), could be important in etiology.
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Future Directions |
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TopAbstractIntroductionClinical CharacteristicsGenetic CharacteristicsInfant Leukemia, DNA...Future DirectionsFundingReferences |
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In an extension of our current study, we are enrolling additional case and control mothers. We are also collecting DNA from infants and mothers to evaluate relationships with genetic polymorphisms. Although this study and others will likely provide clues into the etiology of infant leukemia, it will be important to also consider experimental studies. For example, several groups are developing MLL mouse models (39,40), and it is exciting to consider ways in which environmental exposures gleaned from the observational studies might be incorporated into these systems.
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Funding |
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TopAbstractIntroductionClinical CharacteristicsGenetic CharacteristicsInfant Leukemia, DNA...Future DirectionsFundingReferences |
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National Institutes of Health (CA79940, U10 CA098543 [GenBank] ); Children’s Cancer Research Fund, Minneapolis, MN.
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REFERENCES |
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