1. ¹Department of Toxicology, University of Kentucky College of Medicine, Lexington, KY 40536, USA
2. ²Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY 40536, USA
3. ³Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, KY 40536, USA
4. ⁴James P Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA

Correspondence: Liya Gu, Tel: +1-859-323-0285; Fax: +1-859-323-1059 E-mail: lgu0@email.uky.edu

Received 23 November 2007; Revised 26 November 2007; Accepted 26 November 2007.

Abstract

Acute myeloid leukemia (AML) is an aggressive hematological cancer. Despite therapeutic regimens that lead to complete remission, the vast majority of patients undergo relapse. The molecular mechanisms underlying AML development and relapse remain incompletely defined. To explore whether loss of DNA mismatch repair (MMR) function is involved in AML, we screened two key MMR genes, MSH2 and MLH1, for mutations and promoter hypermethylation in leukemia specimens from 53 AML patients and blood from 17 non-cancer controls. We show here that whereas no amino acid alteration or promoter hypermethylation was detected in all control samples, 18 AML patients exhibited either mutations in MMR genes or hypermethylation in the MLH1 promoter. In vitro functional MMR analysis revealed that almost all the mutations analyzed resulted in loss of MMR function. MMR defects were significantly more frequent in patients with refractory or relapsed AML compared with newly diagnosed patients. These observations suggest for the first time that the loss of MMR function is associated with refractory and relapsed AML and may contribute to disease pathogenesis.