Spontaneous and radiation-induced leukemogenesis of the mouse small eye mutant, Pax6(Sey3H).
Allelic loss on the chromosome 2 is associated with radiation-induced murine acute myeloid leukemia. However, the gene, which contributes mainly to the leukemogenesis has not yet been identified. Expecting any predisposition to acute myeloid leukemia, we performed a radiation leukemogenensis experiment with Pax6(Sey3H), one of the small eye mutants carrying a congenital hemizygosity of the chromosome 2 middle region. A deletion mapping of Pax6(Sey3H) with 50 STS markers indicated that the deleted segment extended between the 106.00 and 111.47 Mb site from the centromere with a length of 5.47 Mb. In the deleted segment, 6 known and 17 novel genes were located. Pax6(Sey3H) mutants that crossed back into C3H/He did not develop myeloid leukemia spontaneously, but they did when exposed to gamma-rays. The final incidence of myeloid leukemia in mutants (25.8%) was as high as that in normal sibs (21.4%). Survival curves of leukemia-bearing mutants shifted toward the left (p = 0.043 by the Log rank test). F1 hybrids of Pax6(Sey3H) with JF1 were less susceptible to radiation than Pax6(Sey3H) onto C3H/He in regard to survival (p = 0.003 and p < 0.00001 for mutants and normal sibs, respectively, by a test of the difference between two proportions). Congenital deletion of the 5.47 Mb segment at the middle region on chromosome 2 alone did not trigger myeloid stem cells to expand clonally in vivo; however, the deletion shortcut the latency of radiation-induced myeloid leukemia.
Nitta
Yumiko
Y
International Radiation Information Center, Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan. yumiko@hiroshima-u.ac.jp
Yoshida
Kazuko
K
Satoh
Kenichi
K
Senba
Kei
K
Nakagata
Naomi
N
Peters
Jo
J
Cattanach
Bruce M
BM
D000818:Animals; D015783:Aniridia / Q000150:complications / Q000473:pathology*; D005136:Eye Proteins; D005720:Gamma Rays; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000150:complications / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000473:pathology*; D007953:Leukemia, Radiation-Induced / Q000150:complications / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D013534:Survival; D016019:Survival Analysis
D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins