1. Evidence for clustered tumour suppressor gene loci on mouse chromosomes 2 and 4 in radiation-induced Acute Myeloid Leukaemia
- Author
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Simon Fitch, Clare Cole, Mays Jawad, Abigail Zanker, Mark Plumb, and Priscilla Lo
- Subjects
Locus (genetics) ,Gene mutation ,Biology ,Bone and Bones ,Chromosomes ,Mice ,hemic and lymphatic diseases ,Animals ,Cluster Analysis ,Genes, Tumor Suppressor ,Radiology, Nuclear Medicine and imaging ,Gene Silencing ,Epigenetics ,Promoter Regions, Genetic ,Gene ,Leukemia, Radiation-Induced ,Genetics ,Base Sequence ,Radiological and Ultrasound Technology ,Chromosome ,Promoter ,Molecular biology ,Mice, Inbred C57BL ,Leukemia, Myeloid, Acute ,Chromosome 4 ,Mice, Inbred CBA ,Electrophoresis, Polyacrylamide Gel ,PAX5 ,Spleen - Abstract
To investigate the influence of genetic and epigenetic factors on allelic loss on chromosomes 2 and 4 in mouse radiation-induced acute myeloid leukaemia (r-AML).r-AML that arose in (CBA/HxC57BL/6)F1xCBA/H and F1xC57BL/6 mice were screened for transcription factor PU1 (also known as SPI-1) gene mutations and methylation of the paired box gene 5 (Pax5) gene promoter. We have increased the statistical significance of a genetic linkage analysis of affected F1xCBA/H mice to test for linkage to loci implicated directly or indirectly with r-AML-susceptibility.There was a statistically significant difference ( p10-4) in the frequency of PU1 gene mutations in F1xCBA/H and F1xC57BL/6 r-AML, implicating a second linked but genotype-dependent myeloid leukaemia suppressor gene on chromosome 2. A suggestive CBA/H r-AML-resistance locus maps within 10 cM of the minimally deleted region on chromosome 4. The Pax5 gene promoter is subject to ongoing subclonal promoter methylation in the r-AML, evidence that Pax5 gene silencing confers a selective advantage during clonal expansion in vivo.Allelic loss in mouse r-AML and subsequent tumour suppressor gene mutation (PU1) or silencing (Pax5) is strongly influenced by genetic background and/or epigenetic factors, and driven by in vivo clonal selection.
- Published
- 2006
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