Leukemia relapse stems from DNA repair function loss

A University of Kentucky research team reports that loss of an important DNA repair function, called DNA mismatch repair (MMR), is responsible for refractory/relapsed Acute Myeloid Leukemia (AML).

The study, "Preferential Loss of Mismatch Repair Function in Refractory and Relapsed Acute Myeloid Leukemia: Potential Contribution to AML Progression," was published in advance online on Jan. 29 by Cell Research of Nature Publishing group. The team was led by Liya Gu, a professor in the Graduate Center for Toxicology of the UK Medical Center.

Acute Myeloid Leukemia (AML) is an aggressive hematological cancer. Although most AML patients achieve complete remission after chemotherapy, they eventually undergo relapse. The molecular basis of the relapse remains unclear.

The researchers looked into blood samples from different development stages of AML patients, i.e., at initial diagnosis, remission (recovered after chemotherapy), relapse, and persistence (no remission because of resistance to chemotherapy), for mutations in MMR genes and found that MMR defects are preferentially associated with relapsed and persistent AML patients.

This study reveals for the first time that loss of MMR function contributes to AML relapse/persistence. In addition, this study has a significant impact on AML and other leukemia treatments. The researchers provide compelling evidence suggesting that AML relapse may be due to minimal residual disease (MRD), a small number of drug-resistant leukemia cells persist in the patient after achieving complete remission.

The researchers found that the phenotype of these drug-resistant MRD cells is similar to cells that have lost the MMR function. Therefore, an understanding of how MMR-deficient cells sensitize to chemotherapeutics would lead to a successful treatment for leukemia patients.

The research team also includes Guogen Mao, Fenghua Yuan, Kimberly Absher, C. Darrell Jennings and Dianna S. Howard of University of Kentucky and Craig T. Jordan at University of Rochester Medical Center.