title: Attenuated DNA damage repair delays therapy-related myeloid neoplasms in a mouse model.
abstract: Therapy-related cancers are potentially fatal late life complications for patients who received radio- or chemotherapy. So far, the mouse model showing reduction or delay of these diseases has not been described. We found that the disruption of Aplf in mice moderately attenuated DNA damage repair and, unexpectedly, impeded myeloid neoplasms after exposure to ionizing radiation (IR). Irradiated mutant mice showed higher rates of p53-dependent cell death, fewer chromosomal translocations, and a delay in malignancy-induced mortality. Simultaneous deficiency of p53 abrogated IR-induced apoptosis and the benefit of impaired DNA repair on mortality in irradiated Aplf–/– mice. Depletion of APLF in non-tumorigenic human cells also markedly reduced the risk of radiation-induced chromosomal aberrations. We therefore conclude that proficient DNA damage repair may promote chromosomal aberrations in normal tissues after irradiation and induce malignant evolution, thus illustrating the potential benefit in sensitizing p53 function by manipulating DNA repair efficiency in cancer patients undergoing genotoxic therapies.
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2M9.
authors.forename: Kit I
authors.initials: KI
authors.lastname: Tong
authors.affiliation: Department of Biochemistry, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama 589-8511, Osaka, Japan.
authors.forename: Kazushige
authors.initials: K
authors.lastname: Ota
authors.affiliation: Department of Biochemistry, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama 589-8511, Osaka, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Komuro
authors.affiliation: Department of Biochemistry, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama 589-8511, Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ueda
authors.affiliation: Department of Pathology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ito
authors.affiliation: Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada M5G 2M9.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 2M9.
authors.forename: C
authors.initials: C
authors.lastname: Anne Koch
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2M9.|Department of Biochemistry, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama 589-8511, Osaka, Japan.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 2M9.|Anti-Aging Center, Kindai University, Higashi-Osaka, Osaka 577-8502, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okada
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology / Q000528:radiation effects; D019046:Bone Marrow Neoplasms / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D016923:Cell Death / Q000528:radiation effects; D002455:Cell Division / Q000528:radiation effects; D002869:Chromosome Aberrations; D033481:Chromosomes, Mammalian / Q000378:metabolism; D002999:Clone Cells; D004249:DNA Damage; D059766:DNA End-Joining Repair / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006410:Hematopoiesis / Q000528:radiation effects; D006801:Humans; D051379:Mice; D009857:Oncogenes; D000075223:Poly-ADP-Ribose Binding Proteins; D034741:RNA, Small Interfering / Q000378:metabolism; D011839:Radiation, Ionizing; D014178:Translocation, Genetic / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C555924:APLF protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase