IDENTIFICATION AND ISOLATION OF C-FMS PROTOONCOGEN FROM F344/N RAT LEUKEMIA

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Understanding the chemically induced or associated occurrence of mononuclear cell leukemia (MNCL) in NTP two-year chronic toxicology and carcinogenesis studies may be complicated by the high background rate of this tumor in aging F344 rats (20 to 30% after 24 months of age). A F344 rat leukemia transplant model has been developed to characterize the biology of this rodent leukemia and to investigate the relationship between age-related, environmental factors, and/or chemically related or modulated (promoted) leukemia. As described previously, karyotype analysis indicates that both spontaneous and serially transplanted leukemia cells have a normal complement of chromosomes (2N=42) with a variant x-subterminal chromosome, but no further details are available on non-random chromosomal changes. Sister chromatid exchange rates in bone marrow cells of aging Fischer 344 rats are about 1.5 times greater than Wistar rats and the background tumor incidence is similarly increased. Studies are in progress to define non-random chromosomal changes (additions, deletions, translocations, etc.) and using high-resolution G-banding techniques and the relationship to the expression of the c-fms protooncogene product (for hematopoietic growth factor receptor, CSF-1). Final results on the identification of c-fms indicate that these rat leukemia cells from both spontaneous (717, untreated, >22 months of age) and transplanted (8/8) leukemias express the fms/CSF-1 receptor as 3.8 kb RNA transcript identical to that expressed by normal rat macrophages. This information is important to the diagnosis and understanding of chemical effects in this rodent model as a surrogate for human exposure to toxic and/or carcinogenic chemicals.