Analysis of expansion of myeloid progenitors in mice to identify leukemic susceptibility genes
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The myeloid progenitor cell compartment (MPC) exhibits pronounced expansion in human myeloid leukemias. It is becoming more apparent that progression of myelodysplastic syndromes and myeloproliferative diseases to acute myelogenous leukemia is the result of defects in progenitor cell maturation. The MPC of bone marrow was analyzed in mice using a cell culture assay for measuring the relative frequency of proliferative myeloid progenitors. Response to the cytokines SCF, IL-3, and GM-CSF was determined by this assay for the leukemic mouse strain BXH-2 and ten other inbred mouse strains. Significant differences were found to exist among ten inbred mouse strains in the nature of their MPC in bone marrow, indicating the presence of genetic polymorphisms responsible for the divergence. The SWR/J and FVB/J strains show consistently low frequencies of myeloid progenitors, while the DBA/2J and SJL/J inbred strains show consistently high frequencies of myeloid progenitors within the bone marrow compartment. In addition, in silico linkage disequilibrium analysis was conducted to identify possible chromosomal regions responsible for the phenotypic variation. Given the importance of this cell compartment in leukemia progression and the soon to be released genomic sequence of 15 mouse strains, these differences may provide a valuable tool for research into leukemia.
KeywordsQuantitative Trait Locus Analysis Inbred Strain Acute Myelogenous Leukemia Stem Cell Factor Myeloid Progenitor
The authors thank Jonathan D. Smith from the Lerner Research Institute for his generous donation of a formatted SNP database. They acknowledge Dr. Linda Siracusa and Dr. Walter Hauck for critical review of this manuscript. This work was supported in part by grants from the NCI. VES was supported in part by NIH training grant T32-CA09678. Some supplies were supplied by a March of Dimes research grant (658).
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