Genetic and epigenetic factors in mouse radiation induced leukaemogenesis
thesisposted on 15.12.2014, 10:38 by Clare Jane Cole
Studies of r-AML susceptible CBA/H and r-AML resistant C57BL/6 inbred mice have provided an animal model that allows investigations into genetic contribution to r-AML (radiation induced acute myeloid leukaemia). This study concentrates on (1) the r-AML susceptibility locus on distal chromosome 1 which overlaps with a genetically determined locus that modulates mouse bone marrow stem cell frequency and (2) a 3.4cM region on chromosome 4 that is deleted in many mouse leukaemias and lymphomas.;Fluorescence activated cell scanning of phenotypically defined bone marrow haemopoietic stem/progenitor cells showed that CBA/H mice have more stem/progenitor cells than C57BL/6 mice. Subsequently analyses of bone marrow cell death and recovery following whole body exposure to an in vivo single acute dose of 3Gy X-rays concluded that this difference is maintained post irradiation, so radiosensitivity is not a confounding factor. Analysis of putative candidate genes located within the chromosome 1 r-AML susceptibility locus did not identify a convincing candidate. However, Pax5 (chromosome 4 candidate TSG) exhibited inactivation in radiation induced malignancies by chromosome deletion and/or Pax5 promoter methylation.;Radiation leukaemogenesis is a multi-stage process resulting from the accumulation of mutations with time. The target cell in r-AML is the HSC and this study proposes that not only is target cell number a cancer risk factor, but HSC proliferation in the immediate aftermath of exposure makes HSCs particularly susceptible to transformation. There is increasing evidence that aberrant differentiation gene expression contributes to leukaemogenesis, and this study also proposes Pax5 inactivation by allelic loss and promoter methylation confers a selective advantage in leukaemogenesis.