Spontaneous and radiation-induced leukemogenesis of the mouse small eye mutant, Pax6(Sey3H)

• Published in: Journal of radiation research 2004-06, Vol.45 (2), p.245
• Main Authors: Nitta, Yumiko, Yoshida, Kazuko, Satoh, Kenichi, Senba, Kei, Nakagata, Naomi, Peters, Jo, Cattanach, Bruce M
• Format: Article
• Language: English
• Subjects: Animals; Aniridia - complications; Aniridia - pathology; Eye Proteins; Gamma Rays; Genetic Predisposition to Disease - genetics; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Intestinal Neoplasms - complications; Intestinal Neoplasms - pathology; Leukemia, Myeloid, Acute - complications; Leukemia, Myeloid, Acute - pathology; Leukemia, Radiation-Induced - complications; Leukemia, Radiation-Induced - pathology; Mice; Mice, Inbred C3H; Mice, Knockout; Paired Box Transcription Factors; PAX6 Transcription Factor; Repressor Proteins; Survival; Survival Analysis
• ISSN: 0449-3060
• DOI: 10.1269/jrr.45.245

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.