The Role of Mutations in the Deoxycytidine Kinase (dCK) Gene in the Development of Acute Myeloid Leukemia (AML) Towards Relapsed and/or Refractory Disease

Abstract

Resistance to chemotherapy is a major problem in the treatment of AML. As CytosineArabinoside (Ara-C) is an important agent in the treatment of Acute Myeloid Leukemia (AML) it is conceivable that leukemic blasts become resistant to Ara-C during the development to relapse/resistant disease. Although several resistance mechanisms are involved in Ara-C metabolism, deoxycytidine kinase (dCK) is of particular interest because it is the rate-limiting enzyme in the phosphorylation process from Ara-C to Ara-CTP. Structural analysis of the dcK gene has revealed mutations which are associated with dCK deficiency and Ara-C resistance in vitro and in vivo. We searched for mutations in thedCK gene in a unique set of paired samples obtained from 31 AML patients at diagnosis and at relapse and/or refractory disease (10 children, 21 adults). Using a RT-PCR to amplify thedCK cDNA, followed by direct sequencing of the PCR product, we did not find any of the previously reported mutations in theWK gene involving codons 20,93,98,99 and 154. Also, we did not find new mutations at time of relapse, nor at diagnosis. These results show that mutations in the dCK gene are scarce and not of major importance for Ara-C resistance in AML patients.