Premium
Loss of heterozygosity at the N‐ras locus in 7,12‐dimethylbenz[a]anthracene‐induced rat leukemia
Author(s) -
Osaka Mitsuhiko,
Matsuo Shinji,
Koh Takashi,
Sugiyama Taketoshi
Publication year - 1997
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/(sici)1098-2744(199704)18:4<206::aid-mc4>3.0.co;2-b
Subject(s) - biology , loss of heterozygosity , 7,12 dimethylbenz[a]anthracene , dmba , allele , point mutation , leukemia , locus (genetics) , wild type , cancer research , genetics , microbiology and biotechnology , transversion , mutation , mutant , carcinogenesis , gene
The 7,12‐dimethylbenz[a]anthracene (DMBA)‐induced rat leukemia model enables scientists to analyze cell altered by carcinogens at various stages of leukemogenesis. We have reported that a consistent type of point mutation, A→T transversion at the second base in codon 61 of the N‐ras gene, was present in this leukemia and that this mutation appeared in bone marrow cells as early as 48 h after a single dose of DMBA. In addition, two leukemia cell lines with the N‐ras mutation had no wild‐type N‐ras allele. Therefore, we examined whether these alterations were essential to the DMBA‐induced leukemias. In the study reported here, we confirmed the occurrence of this N‐ras mutation in 18 (86%) of 21 primary leukemias and loss of the N‐ras wild‐type allele in 12 (67%) of 18 leukemias with the mutated N‐ras. By using microsatellite markers on chromosome 2, loss of heterozygosity (LOH) at the N‐ras locus was observed in eight leukemias, all of which were shown to have lost the wild‐type N‐ras allele by mutant‐allele‐specific amplification. These results suggest that LOH related to loss of the wild‐type N‐ras allele reproducibly occurs in leukemias with the N‐ras mutation. Considering the timing of the N‐ras mutation and LOH, it is likely that the N‐ras mutation is induced early, and cells that have lost the wild‐type N‐ras allele seem to develop into leukemia. We believe that this system provides a suitable model for studying a series of genetic alterations from the earliest stage of carcinogenesis that cannot be approached in human malignancies. Mol. Carcinog. 18:206–212, 1997. © 1997 Wiley‐Liss, Inc.