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Key Dates


  • March 6, 2012 – Online Registration Opens

  • March 12, 2012 – Abstract submission Closes (all abstracts due at this time)

  • March 12, 2012 - New Investigator Award Applications Due

  • April 16, 2012 - Accepted abstracts for Poster Session, New Investigators Announced

  • May 4, 2012 - Hotel Reservations Close

  • May 21, 2012 - Online Registration Closes
Radiation Leukemogenesis in Mice and Humans

*Michael M. Weil, Colorado State University 

Keywords:

Both humans and mice are susceptible to radiation-induced acute myeloid leukemias (rAML) and the mouse has frequently been used to model radiogenic leukemia in man. Two issues of particular interest concerning rAML are whether all similarly radiation exposed individuals are at equal risk or if some individuals are genetically more susceptible than others to radiation leukemogenesis, and whether the incidence of rAML is a function of the background incidence of sporadic AML.

Since there are strain differences in rAML susceptibility in mice (see below) it seems likely there would be genetically sensitive sub-populations for human rAML as well. However, the actual evidence for genetic susceptibility to rAML in humans is sparse and indirect. Familial myelodysplasia (a syndrome that often progresses to AML) and AML have been described indicating that some individuals have a heritable susceptibility to AML, though it’s unknown whether this susceptibility would extend to rAML. Other human heritable syndromes (nevoid basal cell carcinoma, retinoblastoma, Li Fraumeni syndrome, neurofibormatosis type 1 and, perhaps, ataxia-telangiectasia) are associated with susceptibility to radiogenic cancers, though not AML (reviewed in 1). These syndromes are rare, but they do link heritable mutations in specific, well characterized genes to radiogenic cancer susceptibility. Support for a role for genetic susceptibility to radiogenic cancers also comes from a study of meningiomas occurring in families in which multiple members had received radiation for treatment of tinea-capitis which found familial aggregation of affected individuals (2). Additional evidence for genetic susceptibility to radiogenic cancers comes from genetic association studies that link sequence variants in selected genes to the development of certain cancers in individuals from radiation exposed populations (e.g., 3).

Support for genetic susceptibility to radiogenic cancer also comes from comparisons between monozygotic and dizygotic twin pairs of radiobiological endpoints that can be measured ex vivo, and from family studies. These studies have found heritable components of radiation-induced apoptosis, cell cycle delay, chromosomal aberration frequency and gene expression changes, though the relevance of these endpoints to rAML susceptibility is conjectural.

Strain differences in inbred laboratory mice have been used to model interindividual differences in humans. A striking characteristic of radiation-induced AML in mice is its strain dependence, with some inbred strains of mice, such as C3H, CBA, SJL and RFM, being susceptible while others, like C57BL/6, A, and AKR, are resistant. Mapping studies have shown that the strain differences in rAML susceptibility are determined by multiple genes, though none of the genes responsible have been identified. One approach to unraveling complex genetic traits is to break them down into simpler sub-phenotypes. Identifying sub-phenotypes for murine rAML has been facilitated by recent advances in the understanding of the molecular and cytogenetic events involved in leukemogenesis.

Critical mutations in leukemogenesis fall into two broad classes, one leading to a block in hematopoietic differentiation and the other conferring a proliferative or survival advantage (4, 5). In the biological model for murine rAML, the differentiation block results from biallelic loss of the lineage specific transcription factor, PU.1 (designated SfpiI in the mouse) (6). One allele is lost through a cytogenetically detectable deletion on murine chromosome 2, which is likely the direct consequence of irradiation. Chromosome 2 deletions are readily detectable in bone marrow cells of irradiated mice 24 hr post-irradiation. The remaining PU.1 allele is inactivated by point mutation, usually at codon R235. The timing of this mutation and whether it is dependent on the initial radiation exposure are unknown. Loss of PU.1 function prevents terminal differentiation of myeloid progenitors and allows their accumulation. The mutations that lead to acquisition of the capacity for autocrine growth stimulation have not yet been well characterized in murine AML, although there is evidence for autocrine production of GM-CSF and/or IL-3 (7). Based on this biological model, several rAML sub-phenotypes have been proposed including differences between rAML susceptible and resistant strains in the number of target cells at risk, their susceptibility to genomic instability following radiation exposure, and their susceptibility to radiation-induced apoptosis.

Like murine rAML, human rAML is usually characterized by recurrent chromosomal deletions. In humans, the deletions involve loss of chromosomes 5 and/or 7, or deletions of the long arms of these chromosomes (8). These regions are not syntenic with the region of mouse chromosome 2 deleted in murine rAML and evidence for inactivation of PU.1 in human AML is limited and controversial. While chromosome 5 and 7 deletions are also a cytogenetic characteristic of human AML resulting from treatment with alkylating agents, they are not a common feature of sporadic AML which are more commonly associated with translocations. This cytogenetic distinction between rAML and sporadic AML suggests they may arise through different mechanisms and could be regarded as separate disorders. If so, the use of relative risk assessments for rAML may not be valid. References 1. R. A. Kleinerman, Radiation-sensitive genetically susceptible pediatric sub-populations. Pediatr. Radiol. 39 Suppl 1, S27-S31 (2009). 2. P. Flint-Richter and S. Sadetzki, Genetic predisposition for the development of radiation-associated meningioma: an epidemiological study. Lancet Oncol. 8, 403-410 (2007). 3. P. Bhatti, J. P. Struewing, B. H. Alexander, M. Hauptmann, L. Bowen, L. H. Mateus-Pereira, M. A. Pineda, S. L. Simon, R. M. Weinstock and others, Polymorphisms in DNA repair genes, ionizing radiation exposure and risk of breast cancer in U.S. Radiologic technologists. Int. J. Cancer 122, 177-82. (2008). 4. L. M. Kelly and D. G. Gilliland, Genetics of myeloid leukemias. Annu. Rev. Genomics Hum. Genet. 3, 179-198 (2002). 5. D. Metcalf, The Charlotte Friend Memorial Lecture. The role of hematopoietic growth factors in the development and suppression of myeloid leukemias. Leukemia 11, 1599-1604 (1997). 6. W. D. Cook, B. J. McCaw, C. Herring, D. L. John, S. J. Foote, S. L. Nutt, and J. M. Adams, PU.1 is a suppressor of myeloid leukemia, inactivated in mice by gene deletion and mutation of its DNA binding domain. Blood 104, 3437-3444 (2004). 7. D. Metcalf, A. Dakic, S. Mifsud, L. Di Rago, L. Wu, and S. Nutt, Inactivation of PU.1 in adult mice leads to the development of myeloid leukemia. Proc. Natl. Acad. Sci. U S A 103, 1486-1491 (2006). 8. S. M. Smith, M. M. Le Beau, D. Huo, T. Karrison, R. M. Sobecks, J. Anastasi, J. W. Vardiman, J. D. Rowley, and R. A. Larson, Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood 102, 43-52 (2003).

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