Linking pesticide exposure with pediatric leukemia: Potential underlying mechanisms

International Journal of Molecular Sciences

Volumn 17, Issue 4, 2016, Pages

  Hernández, Antonio F ^a   Menéndez, Pablo ^b,c  

^a UNIVERSITY OF GRANADA   (Spain)

^b UNIVERSITY OF BARCELONA   (Spain)

^c INSTITUCIÓ CATALANA DE RECERCA I ESTUDIS AVANÇATS ICREA   (Spain)

Author keywords

Chromosomal rearrangements; DNA double strand break; Hematopoietic stem progenitor cells; Infant and childhood leukemia; Oxidative stress; Pesticides; Topoisomerase II

Indexed keywords

ACETYLCHOLINESTERASE; CYCLIN DEPENDENT KINASE INHIBITOR 1A; CYCLIN DEPENDENT KINASE INHIBITOR 1C; DNA TOPOISOMERASE (ATP HYDROLYSING); PESTICIDE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN BCL 2; PROTEIN C FOS; PROTEIN KINASE B; PROTEIN P53; TRANSCRIPTION FACTOR RUNX1;

CANCER RISK; CELL CYCLE ARREST; CELL DIFFERENTIATION; CELL PROLIFERATION; CHILDHOOD LEUKEMIA; CHROMOSOME TRANSLOCATION; DOUBLE STRANDED DNA BREAK; EXPOSURE; GENETIC ASSOCIATION; GENETIC POLYMORPHISM; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; GENOTYPE ENVIRONMENT INTERACTION; HEMATOPOIETIC STEM CELL; HORMONE METABOLISM; HUMAN; LEUKEMOGENESIS; PHENOTYPE; REVIEW; CHEMISTRY; CHILD; CHROMOSOME ABERRATION; DRUG EFFECTS; LEUKEMIA; METABOLISM;

ACETYLCHOLINESTERASE; CHILD; CHROMOSOME ABERRATIONS; DNA BREAKS, DOUBLE-STRANDED; DNA TOPOISOMERASES, TYPE II; HUMANS; LEUKEMIA; PESTICIDES;

EID: 84962073985     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms17040461     Document Type: Review

References (106)

1. Hunger, S.P.; Mullighan, C.G. Acute lymphoblastic leukemia in children. N. Engl. J. Med. 2015, 373, 1541-1552
2. World Health Organization. Incidence of Childhood Leukemia, an ENHIS Fact Sheet, 2009. Available online: http://www.euro.who.int/__data/assets/pdf_file/0005/97016/4.1.-Incidence-of-childhood-leukaemia-EDITED_layouted.pdf?ua=1 (accessed on 10 February 2016)
3. Wiemels, J. Perspectives on the causes of childhood leukemia. Chem. Biol. Interact. 2012, 196, 59-67
4. Pandita, A.; Harish, R.; Digra, S.K.; Raina, A.; Sharma, A.A.; Koul, A. Molecular cytogenetics in childhood acute lymphoblastic leukemia: A hospital-based observational study. Clin. Med. Insights Oncol. 2015, 9, 39-42
5. Yohe, S. Molecular genetic markers in acute myeloid leukemia. J. Clin. Med. 2015, 4, 460-478
6. Wang, L.D.; Wagers, A.J. Dynamic niches in the origination and differentiation of haematopoietic stem cells. Nat. Rev. Mol. Cell Biol. 2011, 12, 643-655
7. Emerenciano, M.; Koifman, S.; Pombo-de-Oliveira, M.S. Acute leukemia in early childhood. Braz. J. Med. Biol. Res. 2007, 40, 749-760
8. Pui, C.H.; Robison, L.L.; Look, A.T. Acute lymphoblastic leukemia. Lancet 2008, 371, 1030-1043
9. Greaves, M. Infection, immune responses and the etiology of childhood leukemia. Nat. Rev. Cancer 2006, 6, 193-203
10. Greaves, M.; Müschen, M. Infection and the perils of B-cell activation. Cancer Discov. 2015, 5, 1244-1246
11. Martín-Lorenzo, A.; Hauer, J.; Vicente-Dueñas, C.; Auer, F.; González-Herrero, I.; García-Ramírez, I.; Ginzel, S.; Thiele, R.; Constantinescu, S.N.; Bartenhagen, C.; et al. Infection exposure is a causal factor in B-cell precursor acute lymphoblastic leukemia as a result of Pax5-inherited susceptibility. Cancer Discov. 2015, 5, 1328-1343
12. Chen, M.; Chang, C.H.; Tao, L.; Lu, C. Residential exposure to pesticide during childhood and childhood cancers: A meta-analysis. Pediatrics 2015, 136, 719-729
13. Ntzani, E.E.; Chondrogiorgi, M.; Ntritsos, G.; Evangelou, E.; Tzoulaki, I. Literature Review on Epidemiological Studies Linking Exposure to Pesticides and Health Effects. Available online: http://www.efsa.europa.eu/sites/default/files/scientific_output/files/main_documents/497e.pdf (accessed on 25 March 2016)
14. Lu, C.; Liu, X.; Liu, C.; Wang, J.; Li, C.; Liu, Q.; Li, Y.; Li, S.; Sun, S.; Yan, J.; et al. Chlorpyrifos induces MLL translocations through caspase 3-dependent genomic instability and topoisomerase II inhibition in human fetal liver hematopoietic stem cells. Toxicol. Sci. 2015, 147, 588-606
15. Alexander, F.E.; Patheal, S.L.; Biondi, A.; Brandalise, S.; Cabrera, M.E.; Chan, L.C.; Chen, Z.; Cimino, G.; Cordoba, J.C.; Gu, L.J.; et al. Transplacental chemical exposure and risk of infant leukemia with MLL gene fusion. Cancer Res. 2001, 61, 2542-2546
16. Pombo-de-Oliveira, M.S.; Koifman, S.; Brazilian Collaborative Study Group of Infant Acute Leukemia. Infant acute leukemia and maternal exposures during pregnancy. Cancer Epidemiol. Biomark. Prev. 2006, 15, 2336-2341
17. Cavalieri, E.L.; Stack, D.E.; Devanesan, P.D.; Todorovic, R.; Dwivedy, I.; Higginbotham, S.; Johansson, S.L.; Patil, K.D.; Gross, M.L.; Gooden, J.K.; et al. Molecular origin of cancer: Catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc. Natl. Acad. Sci. USA 1997, 94, 10937-10942
18. Ferreira, J.D.; Couto, A.C.; Pombo-de-Oliveira, M.S.; Koifman, S.; Brazilian Collaborative Study Group of Infant Acute Leukemia. In utero pesticide exposure and leukemia in Brazilian children <2 years of age. Environ. Health Perspect. 2013, 121, 269-275
19. Ding, G.; Shi, R.; Gao, Y.; Zhang, Y.; Kamijima, M.; Sakai, K.; Wang, G.; Feng, C.; Tian, Y. Pyrethroid pesticide exposure and risk of childhood acute lymphocytic leukemia in Shanghai. Environ. Sci. Technol. 2012, 46, 13480-13487
20. Metayer, C.; Colt, J.S.; Buffler, P.A.; Reed, H.D.; Selvin, S.; Crouse, V.; Ward, M.H. Exposure to herbicides in house dust and risk of childhood acute lymphoblastic leukemia. J. Expo. Sci. Environ. Epidemiol. 2013, 23, 363-370
21. Ma, X.M.; Buffler, P.A.; Gunier, R.B.; Dahl, G.; Smith, M.T.; Reinier, K.; Reynolds, P. Critical windows of exposure to household pesticides and risk of childhood leukemia. Environ. Health Perspect. 2002, 110, 955-960
22. Slater, M.E.; Linabery, A.M.; Spector, L.G.; Johnson, K.J.; Hilden, J.M.; Heerema, N.A.; Robison, L.L.; Ross, J.A. Maternal exposure to household chemicals and risk of infant leukemia: A report from the Children’s Oncology Group. Cancer Causes Control 2011, 22, 1197-1204
23. Turner, M.C.; Wigle, D.T.; Krewski, D. Residential pesticides and childhood leukemia: A systematic review and meta-analysis. Environ. Health Perspect. 2010, 118, 33-41
24. Bailey, H.D.; Fritschi, L.; Infante-Rivard, C.; Glass, D.C.; Miligi, L.; Dockerty, J.D.; Lightfoot, T.; Clavel, J.; Roman, E.; Spector, L.G.; et al. Parental occupational pesticide exposure and the risk of childhood leukemia in the offspring: Findings from the childhood leukemia international consortium. Int. J. Cancer 2014, 135, 2157-2172
25. Bailey, H.D.; Infante-Rivard, C.; Metayer, C.; Clavel, J.; Lightfoot, T.; Kaatsch, P.; Roman, E.; Magnani, C.; Spector, L.G.; ThPetridou, E.; et al. Home pesticide exposures and risk of childhood leukemia: Findings from the childhood leukemia international consortium. Int. J. Cancer 2015, 137, 2644-2663
26. Rahden-Staron, I. The inhibitory effect of the fungicides captan and captafol on eukaryotic topoisomerases in vitro and lack of recombinagenic activity in the wing spot test of Drosophila melanogaster. Mutat. Res. 2002, 518, 205-213
27. Rahden-Staro n, I.; Czeczot, H.; Kowalska-Loth, B. The ability of thiram to inhibit eukaryotic topoisomerase II and to damage DNA. Acta Biochim. Pol. 1993, 40, 51-53
28. Boros, L.G.; Williams, R.D. Isofenphos induced metabolic changes in K562 myeloid blast cells. Leuk. Res. 2001, 25, 883-890
29. Williams, R.D.; Boros, L.G.; Kolanko, C.J.; Jackman, S.M.; Eggers, T.R. Chromosomal aberrations in human lymphocytes exposed to the anticholinesterase pesticide isofenphos with mechanisms of leukemogenesis. Leuk. Res. 2004, 28, 947-958
30. Zhang, X.; Wallace, A.D.; Du, P.; Lin, S.; Baccarelli, A.A.; Jiang, H.; Jafari, N.; Zheng, Y.; Xie, H.; Soares, M.B.; et al. Genome-wide study of DNA methylation alterations in response to diazinon exposure in vitro. Environ. Toxicol. Pharmacol. 2012, 34, 959-968
31. Ukpebor, J.; Llabjani, V.; Martin, F.L.; Halsall, C.J. Sublethal genotoxicity and cell alterations by organophosphorus pesticides in MCF-7 cells: Implications for environmentally relevant concentrations. Environ. Toxicol. Chem. 2011, 30, 632-639
32. Sirma, S.; Agaoglu, L.; Yildiz, I.; Cayli, D.; Horgusluoglu, E.; Anak, S.; Yuksel, L.; Unuvar, A.; Celkan, T.; Apak, H.; et al. NAD(P)H:quinine oxidoreductase 1 null genotype is not associated with pediatric de novo acute leukemia. Pediatr. Blood Cancer 2004, 43, 568-570
33. Sanjuan-Pla, A.; Bueno, C.; Prieto, C.; Acha, P.; Stam, R.W.; Marschalek, R.; Menéndez, P. Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia. Blood 2015, 126, 2676-2685
34. Das, P.M.; Singal, R. DNA methylation and cancer. J. Clin. Oncol. 2004, 22, 4632-4642
35. Kamdar, K.Y.; Krull, K.R.; El-Zein, R.A.; Brouwers, P.; Potter, B.S.; Harris, L.L.; Holm, S.; Dreyer, Z.; Scaglia, F.; Etzel, C.J.; et al. Folate pathway polymorphisms predict deficits in attention and processing speed after childhood leukemia therapy. Pediatr. Blood Cancer 2011, 57, 454-460
36. Sharp, L.; Little, J. Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: A HuGE review. Am. J. Epidemiol. 2004, 159, 423-443
37. Duncan, T.M.; Reed, M.C.; Nijhout, H.F. The relationship between intracellular and plasma levels of folate and metabolites in the methionine cycle: A model. Mol. Nutr. Food Res. 2013, 57, 628-636
38. Lightfoot, T.J.; Johnston, W.T.; Painter, D.; Simpson, J.; Roman, E.; Skibola, C.F.; Smith, M.T.; Allan, J.M.; Taylor, G.M.; United Kingdom Childhood Cancer Study. Genetic variation in the folate metabolic pathway and risk of childhood leukemia. Blood 2010, 115, 3923-3929
39. Franco, R.F.; Simões, B.P.; Tone, L.G.; Gabellini, S.M.; Zago, M.A.; Falcão, R.P. The methylenetetrahydrofolate reductase C677T gene polymorphism decreases the risk of childhood acute lymphocytic leukemia. Br. J. Haematol. 2001, 115, 616-618
40. Garte, S.; Taioli, E.; Crosti, F.; Sainati, L.; Barisone, E.; Luciani, M.; Jankovic, M.; Biondi, A.G. Deletion of parental GST genes as a possible susceptibility factor in the etiology of infant leukemia. Leuk. Res. 2000, 24, 971-974
41. Chokkalingam, A.P.; Metayer, C.; Scelo, G.A.; Chang, J.S.; Urayama, K.Y.; Aldrich, M.C.; Guha, N.; Hansen, H.M.; Dahl, G.V.; Barcellos, L.F.; et al. Variation in xenobiotic transport and metabolism genes, household chemical exposures, and risk of childhood acute lymphoblastic leukemia. Cancer Causes Control. 2012, 23, 1367-1375
42. Buffler, P.A.; Kwan, M.L.; Reynolds, P.; Urayama, K.Y. Environmental and genetic risk factors for childhood leukemia: Appraising the evidence. Cancer Investig. 2005, 23, 60-75
43. Sherborne, A.L.; Hemminki, K.; Kumar, R.; Bartram, C.R.; Stanulla, M.; Schrappe, M.; Petridou, E.; Semsei, A.F.; Szalai, C.; Sinnett, D.; et al. Rationale for an international consortium to study inherited genetic susceptibility to childhood acute lymphoblastic leukemia. Haematologica 2011, 96, 1049-1054
44. Sedelnikova, O.A.; Redon, C.E.; Dickey, J.S.; Nakamura, A.J.; Georgakilas, A.G.; Bonner, W.M. Role of oxidatively induced DNA lesions in human pathogenesis. Mutat. Res. 2010, 704, 152-159
45. Esperanza, M.; Cid, Á.; Herrero, C.; Rioboo, C. Acute effects of a prooxidant herbicide on the microalga Chlamydomonas reinhardtii: Screening cytotoxicity and genotoxicity endpoints. Aquat. Toxicol. 2015, 165, 210-221
46. Guanggang, X.; Diqiu, L.; Jianzhong, Y.; Jingmin, G.; Huifeng, Z.; Mingan, S.; Liming, T. Carbamate insecticide methomyl confers cytotoxicity through DNA damage induction. Food Chem. Toxicol. 2013, 53, 352-358
47. Muniz, J.F.; McCauley, L.; Scherer, J.; Lasarev, M.; Koshy, M.; Kow, Y.W.; Nazar-Stewart, V.; Kisby, G.E. Biomarkers of oxidative stress and DNA damage in agricultural workers: A pilot study. Toxicol. Appl. Pharmacol. 2008, 227, 97-107
48. Ojha, A.; Srivastava, N. In vitro studies on organophosphate pesticides induced oxidative DNA damage in rat lymphocytes. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 2014, 761, 10-17
49. Kryston, T.B.; Georgiev, A.B.; Pissis, P.; Georgakilas, A.G. Role of oxidative stress and DNA damage in human carcinogenesis. Mutat. Res. 2011, 711, 193-201
50. Hernández, A.F.; Lacasaña, M.; Gil, F.; Rodríguez-Barranco, M.; Pla, A.; López-Guarnido, O. Evaluation of pesticide-induced oxidative stress from a gene-environment interaction perspective. Toxicology 2013, 307, 95-102
51. Mostafalou, S.; Abdollahi, M. Pesticides and human chronic diseases: Evidences, mechanisms, and perspectives. Toxicol. Appl. Pharmacol. 2013, 268, 157-177
52. Woodbine, L.; Brunton, H.; Goodarzi, A.A.; Shibata, A.; Jeggo, P.A. Endogenously induced DNA double strand breaks arise in heterochromatic DNA regions and require ataxia telangiectasia mutated and Artemis for their repair. Nucleic Acids Res. 2011, 39, 6986-6997
53. Gupta, S.C.; Mishra, M.; Sharma, A.; Deepak Balaji, T.G.; Kumar, R.; Mishra, R.K.; Chowdhuri, D.K. Chlorpyrifos induces apoptosis and DNA damage in Drosophila through generation of reactive oxygen species. Ecotoxicol. Environ. Saf. 2010, 73, 1415-1423
54. Dillon, L.W.; Burrow, A.A.; Wang, Y.H. DNA instability at chromosomal fragile sites in cancer. Curr. Genom. 2010, 11, 326-337
55. Thys, R.G.; Lehman, C.E.; Pierce, L.C.; Wang, Y.H. Environmental and chemotherapeutic agents induce breakage at genes involved in leukemia-causing gene rearrangements in human hematopoietic stem/progenitor cells. Mutat. Res. 2015, 779, 86-95
56. Dillon, L.W.; Pierce, L.C.; Lehman, C.E.; Nikiforov, Y.E.; Wang, Y.H. DNA topoisomerases participate in fragility of the oncogene RET. PLoS ONE 2013, 8, e75741
57. Deweese, J.E.; Osheroff, N. The DNA cleavage reaction of topoisomerase II: Wolf in sheep’s clothing. Nucleic Acids Res. 2009, 37, 738-748
58. Nambiar, M.; Raghavan, S.C. How does DNA break during chromosomal translocations? Nucleic Acids Res. 2011, 39, 5813-5825
59. Wiemels, J.L.; Greaves, M. Structure and possible mechanisms of TEL-AML1 gene fusions in childhood acute lymphoblastic leukemia. Cancer Res. 1999, 59, 4075-4082
60. Greaves, M.F.; Wiemels, J. Origins of chromosome translocations in childhood leukemia. Nat. Rev. Cancer 2003, 3, 639-649
61. Meissner, B.; Bartram, T.; Eckert, C.; Trka, J.; Panzer-Gruemayer, R.; Hermanova, I.; Ellinghaus, E.; Franke, A.; Moericke, A.; Schrauder, A.; et al. Frequent and sex-biased deletion of SLX4IP by illegitimate V(D)J-mediated recombination in childhood acute lymphoblastic leukemia. Hum. Mol. Genet. 2014, 23, 590-601
62. Lieber, M.R. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu. Rev. Biochem. 2010, 79, 181-211
63. Murray, J.M.; Messier, T.; Rivers, J.; O’Neill, J.P.; Walker, V.E.; Vacek, P.M.; Finette, B.A. VDJ recombinase-mediated TCR β locus gene usage and coding joint processing in peripheral T cells during perinatal and pediatric development. J. Immunol. 2012, 189, 2356-2364
64. Pinsonneault, R.L.; Vacek, P.M.; O’Neill, J.P.; Finette, B.A. Induction of V(D)J-mediated recombination of an extrachromosomal substrate following exposure to DNA-damaging agents. Environ. Mol. Mutagen. 2007, 48, 440-450
65. Ernst, P.; Wang, J.; Korsmeyer, S.J. The role of MLL in hematopoiesis and leukemia. Curr. Opin. Hematol. 2002, 9, 282-287
66. Marchesi, F.; Girardi, K.; Avvisati, G. Pathogenetic, Clinical, and Prognostic Features of Adult t(4;11)(q21;q23)/MLL-AF4 positive B-cell acute lymphoblastic leukemia. Adv. Hematol. 2011, 2011, 621627
67. Nanya, M.; Sato, M.; Tanimoto, K.; Tozuka, M.; Mizutani, S.; Takagi, M. Dysregulation of the DNA damageresponse and KMT2A rearrangement in fetal liver hematopoietic cells. PLoS ONE 2015, 10, e0144540
68. Strick, R.; Strissel, P.L.; Borgers, S.; Smith, S.L.; Rowley, J.D. Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia. Proc. Natl. Acad. Sci. USA 2000, 97, 4790-4795
69. Sallmyr, A.; Fan, J.; Rassool, F.V. Genomic instability in myeloid malignancies: Increased reactive oxygen species (ROS), DNA double strand breaks (DSBs) and error-prone repair. Cancer Lett. 2008, 270, 1-9
70. Bueno, C.; Catalina, P.; Melen, G.J.; Montes, R.; Sánchez, L.; Ligero, G.; García-Pérez, J.L.; Menendez, P. Etoposide induces MLL rearrangements and other chromosomal abnormalities in human embryonic stem cells. Carcinogenesis 2009, 30, 1628-1637
71. Bueno, C.; Montes, R.; Catalina, P.; Rodríguez, R.; Menendez, P. Insights into the cellular origin and etiology of the infant pro-B acute lymphoblastic leukemia with MLL-AF4 rearrangement. Leukemia 2011, 25, 400-410
72. Eguchi, M.; Eguchi-Ishimae, M.; Knight, D.; Kearney, L.; Slany, R.; Greaves, M. MLL chimeric protein activation renders cells vulnerable to chromosomal damage: An explanation for the very short latency of infant leukemia. Genes Chromosom. Cancer 2006, 45, 754-760
73. Felix, C.A. Leukemias related to treatment with DNA topoisomerase II inhibitors. Med. Pediatr. Oncol. 2001, 36, 525-535
74. Menendez, P.; Catalina, P.; Rodríguez, R.; Melen, G.J.; Bueno, C.; Arriero, M.; García-Sánchez, F.; Lassaletta, A.; García-Sanz, R.; García-Castro, J. Bone marrow mesenchymal stem cells from infants with MLL-AF4+ acute leukemia harbor and express the MLL-AF4 fusion gene. J. Exp. Med. 2009, 206, 3131-3141
75. Spector, L.G.; Xie, Y.; Robison, L.L.; Heerema, N.A.; Hilden, J.M.; Lange, B.; Felix, C.A.; Davies, S.M.; Slavin, J.; Potter, J.D.; et al. Maternal diet and infant leukemia: The DNA topoisomerase II inhibitor hypothesis: A report from the children’s oncology group. Cancer Epidemiol. Biomark. Prev. 2005, 14, 651-655
76. Andersson, A.K.; Ma, J.; Wang, J.; Chen, X.; Gedman, A.L.; Dang, J.; Nakitandwe, J.; Holmfeldt, L.; Parker, M.; Easton, J.; et al. St. Jude Children’s Research Hospital-Washington University Pediatric Cancer Genome Project. The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias. Nat. Genet. 2015, 47, 330-337
77. Driessen, E.M.; van Roon, E.H.; Spijkers-Hagelstein, J.A.; Schneider, P.; de Lorenzo, P.; Valsecchi, M.G.; Pieters, R.; Stam, R.W. Frequencies and prognostic impact of RAS mutations in MLL-rearranged acute lymphoblastic leukemia in infants. Haematologica 2013, 98, 937-944
78. Dobbins, S.E.; Sherborne, A.L.; Ma, Y.P.; Bardini, M.; Biondi, A.; Cazzaniga, G.; Lloyd, A.; Chubb, D.; Greaves, M.F.; Houlston, R.S. The silent mutational landscape of infant MLL-AF4 pro-B acute lymphoblastic leukemia. Genes Chromosom.Cancer 2013, 52, 954-960
79. Prelle, C.; Bursen, A.; Dingermann, T.; Marschalek, R. Secondary mutations in t(4;11) leukemia patients. Leukemia 2013, 27, 1425-1427
80. Prieto, C.; Stam, R.W.; Agraz-Doblas, A.; Ballerini, P.; Camos, M.; Castaño, J.; Marschalek, R.; Bursen, A.; Varela, I.; Bueno, C.; et al. Activated KRAS cooperates with MLLAF4 to promote extramedullary engraftment and migration of cord blood CD34+ HSPC but is insufficient to initiate leukemia. Cancer Res. 2016, in press
81. Bardini, M.; Woll, P.S.; Corral, L.; Luc, S.; Wittmann, L.; Ma, Z.; Lo Nigro, L.; Basso, G.; Biondi, A.; Cazzaniga, G.; et al. Clonal variegation and dynamic competition of leukemia-initiating cells in infant acute lymphoblastic leukemia with MLL rearrangement. Leukemia 2015, 29, 38-50
82. Stumpel, D.J.; Schneider, P.; van Roon, E.H.; Pieters, R.; Stam, R.W. Absence of global hypomethylation in promoter hypermethylated Mixed Lineage Leukemia-rearranged infant acute lymphoblastic leukemia. Eur. J. Cancer 2013, 49, 175-184
83. Stam, R.W.; Schneider, P.; Hagelstein, J.A.; van der Linden, M.H.; Stumpel, D.J.; de Menezes, R.X.; de Lorenzo, P.; Valsecchi, M.G.; Pieters, R. Gene expression profiling-based dissection of MLL translocated and MLL germline acute lymphoblastic leukemia in infants. Blood 2010, 115, 2835-2844
84. Bhojwani, D.; Yang, J.J.; Pui, C.H. Biology of childhood acute lymphoblastic leukemia. Pediatr. Clin. N. Am. 2015, 62, 47-60
85. Greaves, M. In utero origins of childhood leukemia. Early Hum. Dev. 2005, 81, 123-129
86. Greaves, M. Childhood leukemia. BMJ 2002, 324, 283-287
87. Papaemmanuil, E.; Rapado, I.; Li, Y.; Potter, N.E.; Wedge, D.C.; Tubio, J.; Alexandrov, L.B.; van Loo, P.; Cooke, S.L.; Marshall, J.; et al. RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia. Nat. Genet. 2014, 46, 116-125
88. Teitell, M.A.; Pandolfi, P.P. Molecular genetics of acute lymphoblastic leukemia. Annu. Rev. Pathol. 2009, 4, 175-198
89. Swaminathan, S.; Klemm, L.; Park, E.; Papaemmanuil, E.; Ford, A.; Kweon, S.M.; Trageser, D.; Hasselfeld, B.; Henke, N.; Mooster, J.; et al. Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia. Nat. Immunol. 2015, 16, 766-774
90. Ma, X.; Does, M.B.; Metayer, C.; Russo, C.; Wong, A.; Buffler, P.A. Vaccination history and risk of childhood leukemia. Int. J. Epidemiol. 2005, 34, 1100-1109
91. Hosking, F.J.; Leslie, S.; Dilthey, A.; Moutsianas, L.; Wang, Y.; Dobbins, S.E.; Papaemmanuil, E.; Sheridan, E.; Kinsey, S.E.; Lightfoot, T.; et al. MHC variation and risk of childhood B-cell precursor acute lymphoblastic leukemia. Blood 2011, 117, 1633-1640
92. Gilboa-Geffen, A.; Hartmann, G.; Soreq, H. Stressing hematopoiesis and immunity: An acetylcholinesterase window into nervous and immune system interactions. Front. Mol. Neurosci. 2012, 5, 30
93. Rosas-Ballina, M.; Olofsson, P.S.; Ochani, M.; Valdés-Ferrer, S.I.; Levine, Y.A.; Reardon, C.; Tusche, M.W.; Pavlov, V.A.; Andersson, U.; Chavan, S.; et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 2011, 334, 98-101
94. Hoogduijn, M.J.; Cheng, A.; Genever, P.G. Functional nicotinic and muscarinic receptors on mesenchymal stem cells. Stem Cells Dev. 2009, 18, 103-112
95. Stephenson, J.; Czepulkowski, B.; Hirst, W.; Mufti, G.J. Deletion of the acetylcholinesterase locus at 7q22 associated with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Leuk. Res. 1996, 20, 235-241
96. Grisaru, D.; Pick, M.; Perry, C.; Sklan, E.H.; Almog, R.; Goldberg, I.; Naparstek, E.; Lessing, J.B.; Soreq, H.; Deutsch, V. Hydrolytic and nonenzymatic functions of acetylcholinesterase comodulate hemopoietic stress responses. J. Immunol. 2006, 176, 27-35
97. Xi, H.J.; Wu, R.P.; Liu, J.J.; Zhang, L.J.; Li, Z.S. Role of acetylcholinesterase in lung cancer. Thorac. Cancer 2015, 6, 390-398
98. Deutsch, V.R.; Pick, M.; Perry, C.; Grisaru, D.; Hemo, Y.; Golan-Hadari, D.; Grant, A.; Eldor, A.; Soreq, H. The stress-associated acetylcholinesterase variant AChE-R is expressed in human CD34+ hematopoietic progenitors and its C-terminal peptide ARP promotes their proliferation. Exp. Hematol. 2002, 30, 1153-1161
99. Soreq, H.; Patinkin, D.; Lev-Lehman, E.; Grifman, M.; Ginzberg, D.; Eckstein, F.; Zakut, H. Antisense oligonucleotide inhibition of acetylcholinesterase gene expression induces progenitor cell expansion and suppresses hematopoietic apoptosis ex vivo. Proc. Natl. Acad. Sci. USA 1994, 91, 7907-7911
100. Shapira, M.; Grant, A.; Korner, M.; Soreq, H. Genomic and transcriptional characterization of the human ACHE locus: Complex involvement with acquired and inherited diseases. Isr. Med. Assoc. J. 2000, 2, 470-473
101. Perry, C.; Sklan, E.H.; Birikh, K.; Shapira, M.; Trejo, L.; Eldor, A.; Soreq, H. Complex regulation of acetylcholinesterase gene expression in human brain tumors. Oncogene 2002, 21, 8428-8441
102. Johnson, E.; Cotter, F.E. Monosomy 7 and 7q-Associated with myeloid malignancy. Blood Rev. 1997, 11, 46-55
103. Heerema, N.A.; Nachman, J.B.; Sather, H.N.; La, M.K.; Hutchinson, R.; Lange, B.J.; Bostrom, B.; Steinherz, P.G.; Gaynon, P.S.; Uckun, F.M.; et al. Deletion of 7p or monosomy 7 in pediatric acute lymphoblastic leukemia is an adverse prognostic factor: A report from the Children’s Cancer Group. Leukemia 2004, 18, 939-947
104. Xie, J.; Jiang, H.; Wan, Y.H.; Du, A.Y.; Guo, K.J.; Liu, T.; Ye, W.Y.; Niu, X.; Wu, J.; Dong, X.Q.; et al. Induction of a 55 kDa acetylcholinesterase protein during apoptosis and its negative regulation by the Akt pathway. J. Mol. Cell. Biol. 2011, 3, 250-259
105. Zhang, X.J.; Greenberg, D.S. Acetylcholinesterase involvement in apoptosis. Front. Mol. Neurosci. 2012, 5, 40
106. Martelli, A.M.; Evangelisti, C.; Chiarini, F.; McCubrey, J.A. The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget 2010, 1, 89-103