APOBEC3 Mutations in Pediatric Leukemia
Abby M. Green, MD, and researchers at the Center for Childhood Cancer Research (CCCR) are investigating the possibility of a link between APOBEC3 mutations and the development of cancer in children, using leukemia as a model.
APOBEC3 enzymes are known to create mutations in viral DNA, rendering them unable to replicate. APOBECs have also been shown to cause mutations in cellular host DNA.
These enzymes are expressed in blood cells and other tissues. When there is a viral challenge, the enzymes are overexpressed in healthy cells to interfere with viral DNA replication.
APOBEC3 enzymes can also interfere with host cellular DNA, potentially contributing to the development of cancer. Some children may be predisposed to dysregulation of APOBEC3 enzyme activity, particularly following a viral infection.
At the CCCR, mouse and in vitro models — as well as pediatric leukemia databases — are being developed to try to elucidate how the DNA in normal cells becomes mutated by APOBEC3, and whether this leads to malignant transformation of the cell. CCCR scientists are also looking at the normal activity of APOBEC3, and how that goes awry in cancer cells.
Researchers are examining whether mice develop leukemia or lymphoma when APOBEC3 enzymes are expressed in hematopoietic cells and trying to determine if APOBEC3 expression occurs prior to the development of cancer or afterwards.
This holds significant promise for targeted therapeutics. Given that some APOBEC3 family members are abnormally expressed in only cancer cells, an agent that targets these enzymes would have limited effects on other tissues.