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Mutational activation of the N-ras oncogene assessed in primary clonogenic
culture of acute myeloid leukemia (AML): implications for the role of N-ras
mutation in AML pathogenesis
A Bashey, R Gill, S Levi, CJ Farr, R Clutterbuck, JL Millar, IB Pragnell and CJ Marshall
Section of Cell and Molecular Biology, Institute of Cancer Research,
Chester Beatty Laboratories, London, UK.
The number of steps involved in the pathogenesis of acute myeloid leukemia
(AML) is unclear. The initiating event would be expected to exist in all
leukemic cells, but subsequent events may be subclonal. If several genetic
events occur, they may cooperate within the same cell or be alternatively
acquired by different subclones. These possibilities cannot be adequately
analyzed in DNA prepared directly from patient specimens. In this study,
N-ras mutations demonstrable in DNA prepared from peripheral blood of 10
patients with AML were examined in primary in vitro colonies
(AML-colony-forming units [CFU]) grown from these patients. Both colonies
containing the mutant gene and colonies containing normal allele only were
obtained from each patient. The proportion of colonies containing no mutant
allele varied among patients (5% to 57%). A subset of mutation containing
colonies appeared to have lost the normal allele in nine of 10 AML cases
analyzed. In the four cases with two N-ras mutations, the two mutations
were found to exist in different subclones. In these cases, macroscopic
colonies (AML- MCFU) were also obtained using an assay system designed to
select for earlier clonogenic cells than in the AML-CFU assay. The N12cys
mutation in AML10 was found in the CFU, but not in the MCFU, and the N12asp
mutation in AML43 was found in the MCFU, but not in the CFU. These results
suggest that N-ras mutation is a postinitiation event in AML that
contributes to the outgrowth of more malignant subclones. Where two
mutations are found in a case of AML, they appear to have been acquired by
separate subclones, which may show different degrees of differentiation.
Volume 79,
Issue 4,
pp. 981-989,
02/15/1992
Copyright © 1992 by The American Society of Hematology
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