APOBEC3 in Pediatric Leukemia: a Biomarker for Sensitivity to PARP Inhibition?

Background

Although treatment of childhood leukemia has greatly improved, many cases are severe and current therapies are inadequate. Leukemia is caused by a collection of mistakes in DNA, the blueprint within every cell. A family of proteins called APOBEC3 has recently been proposed as a cause of mutations in the DNA of cancer cells. These proteins normally act in healthy white blood cells to fight infection by causing harmful mutations in the DNA of viruses. However, APOBEC3 proteins can cause mutations in human DNA which may contribute to cancer. We have found DNA mutations caused by APOBEC3 proteins in pediatric leukemia.  Although mutations caused by APOBEC3 proteins are dangerous in healthy cells, the activity of APOBEC3 proteins may also make cancer cells vulnerable to treatment. Cancer cells die when they accumulate too many DNA mutations that cannot be repaired.

Project Goal

We propose that DNA mutations caused by APOBEC3 proteins makes cancer cells more sensitive to drugs that block DNA repair machinery. We will test this theory by treating leukemia cells that have APOBEC3 proteins with drugs that stop DNA repair. This combination has the potential to provide new treatment options for severe childhood leukemia.