Childhood leukemia – Risk factors and the need for an interdisciplinary research agenda

Childhood leukemia – Risk factors and the need for an interdisciplinary research agenda

Progress in Biophysics and Molecular Biology 107 (2011) 312e314 Contents lists available at SciVerse ScienceDirect Progress in Biophysics and Molecu...

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Progress in Biophysics and Molecular Biology 107 (2011) 312e314

Contents lists available at SciVerse ScienceDirect

Progress in Biophysics and Molecular Biology journal homepage: www.elsevier.com/locate/pbiomolbio

Review

Childhood leukemia e Risk factors and the need for an interdisciplinary research agenda Gunde Ziegelberger*, Anne Dehos, Bernd Grosche, Sabine Hornhardt, Thomas Jung, Wolfgang Weiss Federal Office for Radiation Protection (BfS), Department of Radiation Protection and Health, Ingolstaedter Landstr. 1, 85764 Oberschleissheim, Germany

a r t i c l e i n f o

a b s t r a c t

Article history: Available online 19 September 2011

The International Agency for Research on Cancer (IARC) has classified high as well as low-frequency fields as “possibly carcinogenic to humans” (Group 2B). For high frequency fields the recent assessment is based mainly on weak positive associations described in some epidemiological studies between glioma and acoustic neuroma and the use of mobile and other wireless phones. Also for lowfrequency fields the evidence is based on epidemiological findings revealing a statistic association between childhood leukemia (CL) and low-level magnetic fields. The basic findings are already 10 years old. They have since been supported by further epidemiological studies. However, the knowledge on the main/crucial question of causality has not improved. This fact and in addition the small, but statistically significant increased incidence of CL in the surrounding of German nuclear power plants have motivated the German Office for Radiation Protection (BfS) to work toward a better understanding of the main causes of CL. A long-term strategic research agenda has been developed which builds on an interdisciplinary, international network and aims at clarifying the aetiology of childhood acute lymphoblastic leukemia. Ó 2011 Elsevier Ltd. All rights reserved.

Keywords: Childhood leukemia Aetiology Risk factors Research recommendations

Contents 1. 2.

3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .312 Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .313 2.1. Genetic risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 2.2. Environmental risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 Research recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .313 3.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 3.1.1. Investigation on the prevalence of potentially predisposing chromosomal translocations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 3.1.2. Deep sequencing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 3.1.3. The role of the hematopoietic stem cell (HSC) niche . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 3.2. Animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314 3.2.1. Generation of appropriate mouse models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314 The way forward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .314 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314

1. Introduction Childhood leukemia (CL) is a rare and complex disease, with B-cell precursor acute lymphoblastic leukemia (ALL) being the

Abbreviations: ALL, acute lymphoblastic leukemia; CL, childhood leukemia; GWAS, genome-wide association studies; HSC, hematopoietic stem cell. * Corresponding author. Tel.: þ49 3018 333 2142; fax: þ49 3018 333 2305. E-mail addresses: [email protected], [email protected] (G. Ziegelberger). 0079-6107/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.pbiomolbio.2011.09.010

main leukemia type in the incidence peak ages of 2e5 years. A handful of chromosomal translocations (TEL-AML1, AML1-ETO, MLL-AF4, MLL-ENL, MLL-AF9, E2A-PBX) and DNA aneuploidies are known as initial genetic events converting a hematopoietic precursor or stem cell into a preleukemic clone. Subsequent events must occur to cause an outbreak of the disease. There are some hints that the initial event occurs already in utero (Ford et al., 1993; Gale et al., 1997; Wiemels et al., 1999; Hjalgrim et al., 2003), but data on the prevalence of preleukemic clones in the general

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population are sparse and markedly diverse (Mori et al., 2002; Lausten-Thomsen et al., 2011). 2. Risk factors The predisposing chromosomal aberrations are consequences of misrepaired double-strand breaks, whereas different risk factors (reflecting different mechanisms) are supposed to be responsible for the additional cooperating genetic or epigenetic events. Although quite a number of risk factors has been studied in recent years, it is to date not possible to correlate specific exposures with the different steps of ALL onset. 2.1. Genetic risk factors Studies on genetic susceptibility started several years ago by analysing gene variants in candidate pathways thought to be involved in the pathogenesis of ALL. Examples are the folate metabolism, immune function, xenobiotic metabolism, DNA repair and oxidative stress (Chokkalingam and Buffler, 2008). Later on, genome-wide association studies (GWAS) of a large number of ALL patients revealed novel gene variants, namely IKZF1, ARIDB5, CEBPE and CDKN2A (e.g., Mullighan et al., 2007; Treviño et al., 2009; Prasad et al., 2010; Sherborne et al., 2010), predominately related to B-cell differentiation. Their effects are modest (ORs appr. 1.2e1.5) and it is unclear how they modulate the risk. Interaction with other inherited factors (geneegene interactions) or exogenous exposures such as chemicals, nutrition factors and infectious agents (geneeenvironment interactions) are under investigation. 2.2. Environmental risk factors The increasing incidence rates observed in industrialized countries (Steliarova-Foucher et al., 2006; Linabery and Ross, 2008) point toward a role of modern lifestyle exposures. However, at an ICNIRP/WHO/BfS Workshop on Risk Factors, held in May 2008 in Berlin (Matthes and Ziegelberger, 2008), it was concluded that none of the environmental or genetic risk factors prove to have major explanatory power. The observed risk factors are small, in general less than 2. The total attributable fraction of all risk factors, identified so far, is considered to be less than 10% of the observed incidence rate. Besides ionizing radiation (either relatively high exposures like x-ray examinations during pregnancy or after birth or chronic low-dose exposure like indoor radon) and non-ionizing radiation from various sources (low and high electromagnetic fields) a set of chemicals under suspicion has been investigated in epidemiological studies. Exposure at different periods of life (pre-conception, during pregnancy, after birth) to outdoor and indoor air pollution, pesticides/herbicides have been studied as well as other lifestyle exposures such as alcohol, smoking, diet including folate intake, socioeconomic factors and so on. So far no clear association with any lifestyle factor has been observed, with the exception of heavy birth weight (Caughey and Michels, 2009) and gender. The environmental risk factor discussed most often is infection. Two distinct working hypothesis have been proposed already more than 20 years ago by Kinlen (1988) and Greaves (1988). To some extent they have supported by subsequent epidemiological studies (Urayama et al., 2010; Roman et al., 2007, 2009). It is generally accepted that the immune system and its response to infectious agents plays a key role in the pathogenesis of B-cell precursor ALL (Greaves, 2006; Dahl et al., 2009). Taking all current evidence together, the only established environmental risk factor is still ionizing radiation. The increased incidence of CL near German nuclear facilities (Kaatsch et al., 2008),

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however, cannot be explained by the observed ionizing radiation as the exposure level is far too low (at least a factor of 1000) to be considered directly causative. Similarly, the association with exposure to residential low-frequency magnetic fields (Schuez and Ahlbom, 2008) cannot be explained by our current knowledge of the biological mechanism of non-ionizing radiation. As both observations are based on reliable study designs, the German Office for Radiation Protection (BfS) has taken the necessary steps to clarify the findings. 3. Research recommendations In July 2010, a small expert group, invited by BfS, defined a longterm strategic research agenda toward a better understanding of the main leukemia type in childhood, namely B-cell precursor ALL (Ziegelberger et al., 2011). In short, it includes the following research priorities: 3.1. Human studies 3.1.1. Investigation on the prevalence of potentially predisposing chromosomal translocations The frequency of preleukemic clones (Mori et al., 2002 versus Lausten-Thomsen et al., 2011) in newborns of an industrialized population needs to be verified as this will allow to understand the key role of preleukemic clones (i.e., do they occur naturally and are they normally extinguished by natural processes?). Comparing the prevalence of these clones in populations with different incidence rates will answer the question whether the observed increasing ALL incidence rates in industrialized countries are correlated with an increase of initial or rather of secondary genetic events. One critical hurdle is still the reliable detection of rare preleukemic clones and a set of validated PCR primers has to be developed to detect the most frequent translocations at the genomic level. 3.1.2. Deep sequencing Besides the ongoing GWAS, it is strongly recommended to initiate next-generation sequencing (whole genome or transcriptome sequences, exome capture and sequencing, analyses of the methylome) of ALL cases, as it is already being done for other tumor types (see International Cancer Genome Consortium). GWAS can reveal population-based variations, but deep sequencing can focus on detailed differences and mutations, e.g., of tumor vs. normal cells, which could, at least in part, reflect the effects of the environment. This could help to detect common patterns/footprints possibly correlated to external risk factors (Pleasance et al., 2010). The previous finding that childhood ALL is the consequence of a limited number of genetic alterations (Mullighan et al., 2007) supports the feasibility of identifying the relevant hits. Characterization of the somatic changes by whole-genome sequencing of ALL cases and predisposed children (from 3.1.1) will add new, valuable insights in the development of the disease and might lead to individually optimized treatment. Comparing genome sequences of ALL cases in populations with different incidence rates should reveal population differences and aims at detecting environmental effects. 3.1.3. The role of the hematopoietic stem cell (HSC) niche In a limited number of ALL cases leukemia-specific aberrations have also been found in mesenchymal stem cells of the HSC niche (Shalapour et al., 2010). This observation has to be verified in a larger cohort as it points toward a role of the stromal microenvironment for the origin and maintenance of ALL.

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3.2. Animal models

References

The ultimate goal is to be able to mimic in the mouse the entire molecular, cellular, tissue and organic features of human B-cell ALL, including its initiation, progression, evolution, response to therapy and eventual cure or relapse.

Caughey, R.W., Michels, K.B., 2009. Birth weight and childhood leukemia: a metaanalysis and review of the current evidence. Int. J. Cancer 124 (11), 2658e2670. Chokkalingam, A.P., Buffler, P.A., 2008. Genetic susceptibility to childhood leukemis. Radiat. Prot. Dosimetry 132 (2), 202e211. Dahl, S., Schmidt, L.S., Vestergaard, T., et al., 2009. Allergy and the risk of childhood leukemia: a meta-analysis. Leukemia 23, 2300e2304. Ford, A.M., Ridge, S.A., Cabrera, M.E., et al., 1993. In utero rearrangements in the trothorax-related oncogene in infant leukaemias. Nature 363 (6427), 358e360. Gale, K.B., Ford, A.M., Repp, R., et al., 1997. Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal spots. Proc. Natl. Acad. Sci. U S A 94 (25), 13950e13954. Greaves, M.F., 1988. Speculations on the cause of childhood acute lymphoblastic leukemia. Leukemia 2, 120e125. Greaves, M.F., 2006. Infection, immune responses and the aetiology of childhood leukaemia. Nat. Rev. Cancer 6 (3), 193e203. Hjalgrim, L.L., Westergaard, T., Rostgaard, K., et al., 2003. Birth weight as a risk factor for childhood leukemia: a meta-analysis of 18 epidemiologic studies. Am. J. Epidemiol. 158 (8), 724e735. Kaatsch, P., Spix, C., Schulze-Rath, R., et al., 2008. Leukaemia in young children living in the vicinity of German nuclear power plants. Int. J. Cancer 122, 721e726. Kinlen, L.J., 1988. Evidence for an infective cause of childhood leukaemia: comparison of a Scottish new town with nuclear reprocessing sites in Britain. Lancet 2, 1323e1327. Lausten-Thomsen, U., Madsen, H.O., Vestergaard, T.R., et al., 2011. Prevalence of t(12;21) [ETV6-RUNX1]-positive cells in healthy neonates. Blood 117 (1), 186e189. Linabery, A.M., Ross, J.A., 2008. Trends in childhood cancer incidence in the U.S. (1992e2004). Cancer 112 (2), 416e432. Matthes, R., Ziegelberger, G. (eds.) 2008. Risk factors for childhood leukemia. Proceedings of an ICNIRP Workshop, Berlin, May 5e7, 2008. Radiat. Prot. Dosimetry, Special Issue 132(2). Mori, H., Colman, S.M., Xiao, Z., et al., 2002. Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc. Natl. Acad. Sci. U S A 99, 8242e8247. Mullighan, C.G., Goorha, S., Radtke, I., et al., 2007. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446, 758e764. Pleasance, E.D., Stephens, P.J., O’Meara, S., et al., 2010. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 463, 184e190. Prasad, R.B., Hosking, F.J., Vijayakrishnan, J., et al., 2010. Verification of the susceptibility loci on 7p12.2, 10q21.2, and 14q11.2 in precursor B-cell acute lymphoblastic leukemia of childhood. Blood 115, 1765e1767. Roman, E., Simpson, J., Ansell, P., et al., 2007. Childhood acute lymphoblastic leukemia and infections in the first year of life: a report from the United Kingdom childhood cancer study. Am. J. Epidemiol. 165 (5), 496e504. Roman, E., Simpson, J., Ansell, P., et al., 2009. Infectious proxies and childhood leukaemia: findings from the United Kingdom childhood cancer study (UKCCS). Blood Cells Mol. Dis. 42, 126e128. Schuez, J., Ahlbom, A., 2008. Exposure to electromagnetic fields and the risk of childhood leukemia: a review. Radiat. Prot. Dosimetry 132 (2), 202e211. Shalapour, S., Eckert, C., Seeger, K., et al., 2010. Leukemia-associated genetic aberrations in mesenchymal stem cells of children with acute lymphoblastic leukemia. J. Mol. Med. 88, 249e265. Sherborne, A.L., Hosking, F.J., Prasad, R.B., et al., 2010. Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk. Nat. Genet. 42, 492e494. Steliarova-Foucher, E., Coebergh, J.W., Kaatsch, P., et al., 2006. Eur. J. Cancer 42, 1913e2190. Treviño, L.R., Yang, W., French, D., et al., 2009. Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat. Genet. 41, 1001e1005. Urayama, K.Y., Buffler, P.A., Gallagher, E.R., et al., 2010. A meta-analysis of the association between day-care attendance and childhood acute lymphoblastic leukaemia. Int. J. Epidemiol. 39, 718e732. Wiemels, J.L., Cazzaniga, G., Daniotti, M., et al., 1999. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet 354 (9189), 1499e1503. Ziegelberger, G., Baum, C., Borkhardt, A., et al., 2011. Research recommendations toward a better understanding of the causes of childhood leukemia. Blood Cancer J. 1 e1.

3.2.1. Generation of appropriate mouse models The availability and suitability of existing mouse models have to be checked and, in addition, there is a need for generating several new mouse strains, preferentially by germline-transgenesis. These new strains will be (i) exposed to possible risk factors followed by complete standardized phenotyping and (ii) used for generating a B-cell leukemia model of controlled genetic variability via backcrossing of a susceptible mouse strain with a resistant one. Finally, a cohort of this B-cell leukemia model of genetic variability will be exposed to possible risk factors. Some essential questions on the aetiology of B-cell leukemia as outlined above can only be addressed by combined efforts in an interdisciplinary network. There is a strong necessity for close cooperation between researchers involved in human studies and those generating the B-cell leukemia model. The impact of gene variants identified in human studies has to be verified in the B-cell leukemia model in mice. Similarly, it has to be proven that the mechanisms brought together in this research agenda can quantitatively account for the totality of human data. The construction of novel quasi-mechanistic models will include the recently revealed high developmental plasticity of hematopoietic cells and the role of the microenvironment. 4. The way forward The low incidence of ALL and the expected small relative risk of any related risk factor require large sample sizes and a broad, interdisciplinary, worldwide consortium. Initiatives have already started among epidemiologists (see Childhood Leukemia International Consortium and the International Childhood Cancer Cohort Consortium), but epidemiology alone might not be able to come to final conclusions. The results of the German KiKK-study (Kaatsch et al., 2008) and the consistent finding of a statistical association between low-level magnetic fields and CL have renewed the efforts of radiation experts not only in Germany (see recent recommendations by COMARE in UK and ISRN in France) to pursue the causes of CL. Based on the above research recommendations (Ziegelberger et al., 2011), several pilot studies have been initiated by BfS in 2011. A call for a pilot study for building (or joining) a German birth cohort is currently open and pilot studies for comparing regional ALL differences and for deep sequencing of the first 10 ALL individuals are pursued with high priority. The pilot studies will establish an international and interdisciplinary network which is essential for moving forward in our understanding of the causes of childhood leukemia. It is expected that the main studies will start in 2013.