HIGH-FREQUENCY OF RAS ONCOGENE MUTATION IN CHRONIC MYELOID-LEUKEMIA PATIENTS WITH MYELOBLASTOMA

To determine the role of the mutated RAS oncogene during development into the blast phase, we sequentially analysed RAS oncogene mutations in the bone marrow of 27 patients with chronic myeloid leukemia (CML). DNA from CML patients in chronic and blast phases and nude mouse tumor DNA formed by a tumorigenicity assay (in vivo selection assay) were subjected to the polymerase chain reaction (PCR) and oligonucleotide hybridization. In addition, one patient in the chronic phase and five in the blast phase were also analysed. PCR analysis of DNA from the leukemic patients revealed that 3.6% (1 of 28) and 15.6% (5 of 32) of the patients in the chronic and blast phases, respectively, had RAS mutations. N- or K-RAS oncogene mutations were found mostly in the blast phase (4 of the 5 patients with the RAS oncogene mutation). Of the 5 patients with the RAS oncogene mutation, three developed myeloblastoma, a myeloblast cell tumor, in the blast phase. None of the 28 patients without the RAS mutation developed myeloblastoma. These results suggest that the RAS oncogene mutation occurred in the late stage of the disease and contributed to transformation to the blast phase in some CML patients. The findings also indicate an association between the presence of the RAS mutation and the formation of myeloblastoma.