title: Prenatal origin of chromosomal translocations in acute childhood leukemia: implications and future directions.
abstract: We, and others, have demonstrated an in utero origin for translocations associated with childhood leukemia, with latency periods in some cases exceeding 10 years. The mechanism of generation of most of the translocations is thought to be aberrant repair following abortive apoptosis, rather than V(D)J recombination or exposure to topoisomerase II inhibitors. Folate supplementation may prevent some of the chromosome breakage leading to translocation formation. Translocations t(8;21) and t(12;21) have been shown to occur in the normal population (before birth) at a frequency that is 100-fold greater than the risk of developing the corresponding leukemia. In most instances, additional genetic changes are required for progression to leukemia. Tyrosine kinase receptor (RTK) mutations, which give cells a survival/proliferative advantage, are proposed to act cooperatively with fusion genes, leading to transformation. However, translocations and cooperating RTK mutations have not been identified for all leukemia subtypes, particularly in acute myeloid leukemia. The core binding transcriptional pathway is frequently targeted by translocation in utero. We propose that this pathway is highly sensitive during fetal hematopoiesis and may be targeted by mechanisms other than translocation. For each leukemia subtype it is important to characterize the corresponding leukemic stem cell, which is thought to be the initial target for translocation. This would help to elucidate the molecular pathways involved in the progression from preleukemic clone harboring a translocation to fully disseminated leukemia.
authors.affiliation: Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, California 94720-7360, USA. cmhale@uclink.berkley.edu
authors.forename: Cliona M
authors.initials: CM
authors.lastname: McHale
authors.forename: Martyn T
authors.initials: MT
authors.lastname: Smith
mesh_terms: D000208:Acute Disease; D002648:Child; D005315:Fetal Diseases / Q000235:genetics*; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011296:Prenatal Diagnosis; D014178:Translocation, Genetic
chemical_list: D015514:Oncogene Proteins, Fusion