title: c-myb Heterozygous mice are hypersensitive to 5-fluorouracil and ionizing radiation.
abstract: Hypersensitivity to chemo- and radiotherapy employed during cancer treatment complicates patient management. Identifying mutations in genes that compromise tissue recovery would rationalize treatment and may spare hypersensitive patients undue tissue damage. Genes that govern stem cell homeostasis, survival, and progenitor cell maintenance are of particular interest in this regard. We used wild-type and c-myb knock-out mice as model systems to explore stem and progenitor cell numbers and sensitivity to cytotoxic damage in two radiosensitive tissue compartments, the bone marrow and colon. Because c-myb null mice are not viable, we used c-myb heterozygous mice to test for defects in stem-progenitor cell pool recovery following gamma-radiation and 5-fluorouracil treatment, showing that c-myb(+/-) mice are hypersensitive to both agents. While apoptosis is comparable in mutant and wild-type mice following radiation exposure, the crypt beds of c-myb(+/-) mice are markedly depleted of proliferating cells. Extrapolating from these data, we speculate that acute responses to cytotoxic damage in some patients may also be attributed to compromised c-myb function.
authors.affiliation: Differentiation and Transcription Laboratory, Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, Melbourne 8006, Australia. rob.ramsay@Petermac.org
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ramsay
authors.forename: Suzanne
authors.initials: S
authors.lastname: Micallef
authors.forename: Sally
authors.initials: S
authors.lastname: Lightowler
authors.forename: Michael L
authors.initials: ML
authors.lastname: Mucenski
authors.forename: Theo
authors.initials: T
authors.lastname: Mantamadiotis
authors.forename: Ivan
authors.initials: I
authors.lastname: Bertoncello
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001853:Bone Marrow / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003106:Colon / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D005472:Fluorouracil / Q000494:pharmacology*; D020570:Genes, myb / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006579:Heterozygote; D051379:Mice; D018345:Mice, Knockout; D020598:Proto-Oncogene Proteins c-myb / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing
chemical_list: D020598:Proto-Oncogene Proteins c-myb; D005472:Fluorouracil