Evidence for clustered tumour suppressor gene loci on mouse chromosomes 2 and 4 in radiation-induced acute myeloid leukaemia.
OBJECTIVE
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).


METHODS
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.


RESULTS
There was a statistically significant difference ( p < 10-4) 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.


CONCLUSIONS
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.
Jawad
Mays
M
Department of Genetics, University of Leicester, Leicester, UK.
Cole
Clare
C
Zanker
Abigail
A
Lo
Priscilla
P
Fitch
Simon
S
Plumb
Mark
M
D000818:Animals; D001483:Base Sequence; D001842:Bone and Bones / Q000473:pathology / Q000528:radiation effects; D002875:Chromosomes; D016000:Cluster Analysis; D004591:Electrophoresis, Polyacrylamide Gel; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor / Q000528:radiation effects*; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics*; D007953:Leukemia, Radiation-Induced / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D011401:Promoter Regions, Genetic; D013154:Spleen / Q000473:pathology / Q000528:radiation effects