In this study we also demonstrate that inactivating FPGS mutations constitute a dominant mechanism of antifolate resistance in leukemia cells, illustrated by the fact that all antifolate-resistant cells that were examined harbored inactivating mutations in the ORF of FPGS. We have previously shown (Liani et al., 2003) that loss of FPGS activity is a dominant mechanism of resistance to polyglutamatable-antifolates in leukemia cells and our conclusion was that inactivating mutations are not a common mechanism of loss of FPGS function in antifolate resistance [11]. Here, FPGS is linked to leukemia.