AMPLIFICATION OF THE DIHYDROFOLATE-REDUCTASE GENE IS A MECHANISM OF ACQUIRED-RESISTANCE TO METHOTREXATE IN PATIENTS WITH ACUTE LYMPHOBLASTIC-LEUKEMIA AND IS CORRELATED WITH P53 GENE-MUTATIONS

Although dihydrofolate reductase (DHFR) gene amplification is a common mechanism of resistance to methotrexate (MTX) in tumor cell lines, wi th the exception of a few case reports, the incidence of this phenomen on as a mechanism of MTX resistance in the clinic has not been reporte d. We studied 38 untreated patients and 29 patients in relapse with ac ute lymphoblastic leukemia (ALL) for gene amplification and p53 gene m utations. Three patients were studied both at diagnosis and at each of two relapses after treatment with MTX. Nine of 29 relapsed patients ( 31%) had low-level DHFR gene amplification (two to four gene copies) a ssociated with increased levels of DHFR mRNA and enzyme activity, Of s ignificance was a correlation of gene amplification with p53 mutations in seven of nine relapsed patients (P < .001). Low-level DHFR gene am plification may be an important cause of MTX resistance in ALL and str engthens the concept that mutations in the p53 gene may lead to gene a mplification as a consequence of defective cell cycle control. (C) 199 5 by The American Society of Hematology.