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DNA Damage and Cellular Stress Responses

c-myb Heterozygous Mice Are Hypersensitive to 5-Fluorouracil and Ionizing Radiation¹

¹ Peter MacCallum Cancer Centre, East Melbourne, Australia;
² Institute for Reproduction and Development, Monash Medical Centre, Clayton, Australia; and
³ Division of Pulmonary Biology, Children's Hospital Medical Centre, Cincinnati, Ohio

Requests for reprints: Robert Ramsay, Differentiation and Transcription Laboratory, Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, Locked Bag #1 A' Beckett Street, Melbourne 8006, Australia. Phone: 61-3-9656-1863; Fax: 61-3-9656-3738. E-mail: rob.ramsay{at}Petermac.org

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 -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.

Key Words: c-myb • colon • stem cells • bone marrow

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