Credit: Tom Ellenberger
Researchers say they’ve discovered “an intimate link” between RUNX genes and Fanconi anemia, a finding that also has implications for treating acute myeloid leukemia (AML).
The group found that RUNX1 and RUNX3 interact with Fanconi anemia group D2 (FANCD2), a protein involved in the repair of DNA damage.
The RUNX proteins facilitate the recruitment of FANCD2 to sites of DNA damage in both Fanconi anemia and AML.
Motomi Osato, MD, PhD, of the Cancer Science Institute of Singapore, and his colleagues recounted these findings in Cell Reports.
The researchers began by studying RUNX deficiency in mice. They found that knockdown of both RUNX1 and RUNX3 led to bone marrow failure or myeloproliferative disorders in the mice.
These clinical manifestations are seen in inherited bone marrow failure syndromes such as Fanconi anemia, which is caused by the disruption of gene products that participate in the repair of DNA interstrand crosslinks (ICLs).
With this in mind, the researchers decided to investigate RUNX function in the ICL repair pathway. And they found RUNX proteins play a critical role in the pathway by facilitating the recruitment of FANCD2 to sites of DNA damage.
To explore the clinical relevance of RUNX participation in DNA damage repair, the team conducted experiments in Kasumi-1 and SKNO-1 cells. These AML cell lines express RUNX1-ETO, which is thought to suppress the expression and/or function of RUNX1 and RUNX3 simultaneously.
The researchers showed that Kasumi-1 and SKNO-1 cells were sensitive to the ICL-inducing agent mytomycin C, and knocking down RUNX1-ETO reduced this sensitivity. Depleting RUNX1-ETO also led to increased FANCD2 recruitment to chromatin.
The team said these results suggest that RUNX1-ETO might repress FANCD2 foci formation and ICL repair in AML cells. And they predicted that RUNX dysfunction would sensitize the cells to PARP inhibitors.
So they tested 2 PARP inhibitors—olaparib and rucaparib—in Kasumi-1 cells and observed sensitivity to both drugs. Knocking down RUNX1-ETO partially reduced this sensitivity, while adding mytomycin C increased sensitivity.
“PARP inhibitors have been with us for quite some time, but nobody has realized their application for leukemia,” Dr Osato said. “Our study has shed light on the possibility of a more effective treatment using a combined therapy with PARP inhibitors, which can potentially be extended to other types of common cancers.”
The researchers are now conducting additional drug testing in xenograft models.
