DHFR and acute lymphoblastic leukemia: Methotrexate (MTX) was first introduced to replace aminopterin to treat acute lymphocytic leukemia, which works via inhibiting dihydrofolate reductase (DHFR), a key enzyme required in intracellular folate metabolism, leading to decreased tretrahydrofolate coenzyme level, accordingly achieving the inhibition of thymidylate and the biosynthesis of DNA and purine.