Evidence for complex multigenic inheritance of radiation AML susceptibility in mice revealed using a surrogate phenotypic assay.

Radiation Effects Department, Health Protection Agency, Radiation Protection Division, Chilton, Didcot, Oxfordshire, OX11 0RQ, UK.
Carcinogenesis (Impact Factor: 5.27). 03/2006; 27(2):311-8. DOI: 10.1093/carcin/bgi207
Source: PubMed

ABSTRACT The mapping of genes which affect individual cancer risk is an important but complex challenge. A surrogate assay of susceptibility to radiation-induced acute myeloid leukaemia (AML) in the mouse based on chromosomal radiosensitivity has been developed and validated. This assay was applied to the mapping of radiation-induced AML risk modifier loci by association with microsatellite markers. A region on chromosome (chr) 18 with strong association is identified and confirmed by backcross analysis. Additional loci on chrs 8 and 13 show significant association. A key candidate gene Rbbp8 on chr18 is identified. Rbbp8 is shown to be upregulated in response to X-irradiation in the AML sensitive CBA strain but not AML resistant C57BL/6 strain. This study demonstrates the strength of utilizing surrogate endpoints of cancer susceptibility in the mapping of mouse loci and identifies additional loci that may affect radiation cancer risk.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In spite of extensive research, assessment of potential health risks associated with exposure to low-dose (≤ 0.1 Gy) radiation is still challenging. We evaluated the in vivo induction of genomic instability, expressed as late-occurring chromosome aberrations, in bone-marrow cells of two strains of mouse with different genetic background, i.e. the radiosensitive BALB/cJ and the radioresistant C57BL/6J strains following a whole-body exposure to varying doses of (137)Cs gamma rays (0, 0.05, 0.1, and 1.0 Gy). A total of five mice per dose per strain were sacrificed at various times post-irradiation up to 6 months for sample collections. Three-color fluorescence in situ hybridization for mouse chromosomes 1, 2, and 3 was used for the analysis of stable-aberrations in metaphase-cells. All other visible gross structural-abnormalities involving non-painted-chromosomes were also evaluated on the same metaphase-cells used for scoring the stable-aberrations of painted-chromosomes. Our new data demonstrated in bone-marrow cells from both strains that low doses of low LET-radiation (as low as 0.05 Gy) are incapable of inducing genomic instability but are capable of reducing specific aberration-types below the spontaneous rate with time post-irradiation. However, the results showed the induction of genomic instability by 1.0 Gy of (137)Cs gamma rays in the radiosensitive strain only.
    Dose-Response 01/2012; 10(1):11-36. DOI:10.2203/dose-response.11-002.Rithidech · 1.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Particle radiations could significantly impact astronaut health during space missions. This study quantified the effects of iron ion radiation on lymphocytes in two strains of mice differing in susceptibility to radiation-induced acute myeloid leukemia (AML) and thymic lymphoma (TL): C57BL/6 (AML resistant, TL sensitive) and CBA/Ca (AML sensitive, TL resistant). The animals (n = 60/strain) were irradiated with ⁵⁶Fe(26+) (1 GeV) to total doses of 0, 0.5, 2 and 3 Gray (Gy) at an average dose rate of 1 Gy/min and euthanised on days 4 and 30 thereafter; blood, spleen, and bone marrow were collected for flow cytometry analyses. Cells expressing the following molecules were quantified: Cluster of differentiation (CD) 4, CD8, CD25, CD34, CD71, B220 (isoform of CD45 on B cells), NK1.1 (marker on natural killer or NK cells, C57B mice), panNK (marker on NK cells, CBA mice), and Sca1 (stem cell antigen 1). Exposure to radiation resulted in different distribution patterns in lymphocyte populations and leukocytes expressing activation and progenitor markers in the two mouse strains. Significant main effects were dependent upon strain, as well as radiation dose, body compartment, and time of assessment. Especially striking differences were noted on day 4 after 3 Gy irradiation, including in the CD4:CD8 ratio [blood, C57 (2.83 ± 0.25) vs. CBA (6.19 ± 0.24); spleen, C57 (2.29 ± 0.12) vs. CBA (4.98 ± 0.22)], %CD25(+) mononuclear cells in bone marrow [C57 (5.62 ± 1.19) vs. CBA (12.45 ± 0.93)] and %CD34(+)Sca1(+) cells in bone marrow [CD45¹° gate, C57 (2.72 ± 0.74) vs. CBA (21.44 ± 0.73)]. The results show that genetic background, as well as radiation dose and time post-exposure, had a profound impact on lymphocyte populations, as well as other leukocytes, after exposure to iron ion radiation.
    International Journal of Radiation Biology 11/2010; 87(1):8-23. DOI:10.3109/09553002.2010.518203 · 1.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The transcription factor PU.1, encoded by the murine Sfpi1 gene (SPI1 in humans), is a member of the Ets transcription factor family and plays a vital role in commitment and maturation of the myeloid and lymphoid lineages. Murine studies directly link primary acute myeloid leukaemia (AML) and decreased PU.1 expression in specifically modified strains. Similarly, a radiation-induced chromosome 2 deletion and subsequent Sfpi1 point mutation in the remaining allele lead to murine radiation-induced AML. Consistent with murine data, heterozygous deletion of the SPI1 locus and mutation of the -14 kilobase SPI1 upstream regulatory element were previously described in human primary AML, although they are rare events. Other mechanisms linked to PU.1 downregulation in human AML include TP53 deletion, Flt3-ITD mutation and the recurrent AML1-ETO [t(8;21)] and PML-RARA [t(15;17)] translocations. This review provides an up-to-date overview on our current understanding of the involvement of PU.1 in the initiation and development of radiation-induced AML, together with recommendations for future murine and human studies. © The Author 2014. Published by Oxford University Press.
    Carcinogenesis 03/2015; 36(4). DOI:10.1093/carcin/bgv016 · 5.27 Impact Factor