The thymidine dideoxynucleoside analog, alovudine, inhibits the mitochondrial DNA polymerase γ, impairs oxidative phosphorylation and promotes monocytic differentiation in acute myeloid leukemia
Dana Yehudai,
Sanduni U. Liyanage,
Rose Hurren,
Biljana Rizoska,
Mark Albertella,
Marcela Gronda,
Danny V Jeyaraju,
Xiaoming Wang,
Samir H. Barghout,
Neil MacLean,
Thirushi P. Siriwardena,
Yulia Jitkova,
Paul Targett-Adams,
Aaron D. Schimmer
Affiliations
Dana Yehudai
Princess Margaret Cancer Centre, University Health Network, ON, Canada;Medivir AB, Huddinge, Sweden
Sanduni U. Liyanage
Princess Margaret Cancer Centre, University Health Network, ON, Canada
Rose Hurren
Princess Margaret Cancer Centre, University Health Network, ON, Canada
Biljana Rizoska
Medivir AB, Huddinge, Sweden
Mark Albertella
Princess Margaret Cancer Centre, University Health Network, ON, Canada
Marcela Gronda
Princess Margaret Cancer Centre, University Health Network, ON, Canada
Danny V Jeyaraju
Princess Margaret Cancer Centre, University Health Network, ON, Canada
Xiaoming Wang
Princess Margaret Cancer Centre, University Health Network, ON, Canada
Samir H. Barghout
Princess Margaret Cancer Centre, University Health Network, ON, Canada
Neil MacLean
Princess Margaret Cancer Centre, University Health Network, ON, Canada
Thirushi P. Siriwardena
Princess Margaret Cancer Centre, University Health Network, ON, Canada
Yulia Jitkova
Princess Margaret Cancer Centre, University Health Network, ON, Canada
Paul Targett-Adams
Princess Margaret Cancer Centre, University Health Network, ON, Canada
Aaron D. Schimmer
Princess Margaret Cancer Centre, University Health Network, ON, Canada
Mitochondrial DNA encodes 13 proteins that comprise components of the respiratory chain that maintain oxidative phosphorylation. The replication of mitochondrial DNA is performed by the sole mitochondrial DNA polymerase γ. As acute myeloid leukemia (AML) cells and stem cells have an increased reliance on oxidative phosphorylation, we sought to evaluate polymerase γ inhibitors in AML. The thymidine dideoxynucleoside analog, alovudine, is an inhibitor of polymerase γ. In AML cells, alovudine depleted mitochondrial DNA, reduced mitochondrial encoded proteins, decreased basal oxygen consumption, and decreased cell proliferation and viability. To evaluate the effects of polymerase γ inhibition with alovudine in vivo, mice were xenografted with OCI-AML2 cells and then treated with alovudine. Systemic administration of alovudine reduced leukemic growth without evidence of toxicity and decreased levels of mitochondrial DNA in the leukemic cells. We also showed that alovudine increased the monocytic differentiation of AML cells. Genetic knockdown and other chemical inhibitors of polymerase γ also promoted AML differentiation, but the effects on AML differentiation were independent of reductions in oxidative phosphorylation or respiratory chain proteins. Thus, we have identified a novel mechanism by which mitochondria regulate AML fate and differentiation independent of oxidative phosphorylation. Moreover, we highlight polymerase γ inhibitors, such as alovudine, as novel therapeutic agents for AML.
