Page 117 - 2019_05-HaematologicaMondo-web

Acute Myeloid Leukemia
The thymidine dideoxynucleoside analog, alovudine, inhibits the mitochondrial DNA polymerase γ, impairs oxidative phosphorylation and promotes monocytic differentiation in acute myeloid leukemia
Ferrata Storti Foundation
Haematologica 2019 Volume 104(5):963-972
Dana Yehudai,1,2 Sanduni U. Liyanage,1 Rose Hurren,1 Biljana Rizoska,2 Mark Albertella,1 Marcela Gronda,1 Danny V Jeyaraju,1 Xiaoming Wang,1 Samir H. Barghout,1 Neil MacLean,1 Thirushi P. Siriwardena,1 Yulia Jitkova,1 Paul Targett-Adams1 and Aaron D. Schimmer1
1Princess Margaret Cancer Centre, University Health Network, ON, Canada and 2Medivir AB, Huddinge, Sweden
ABSTRACT
Mitochondrial DNA encodes 13 proteins that comprise compo- nents of the respiratory chain that maintain oxidative phospho- rylation. 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 oxida- tive 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 mitochondr- ial DNA, reduced mitochondrial encoded proteins, decreased basal oxy- gen consumption, and decreased cell proliferation and viability. To eval- uate the effects of polymerase γ inhibition with alovudine in vivo, mice were xenografted with OCI-AML2 cells and then treated with alovu- dine. 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.
Introduction
Acute myeloid leukemia (AML) is a hematologic malignancy with a poor prog- nosis, characterized by clonal, pathological and often poorly differentiated hematopoietic cells that infiltrate the bone marrow (BM), blood and extra- medullary tissues. In spite of some recent new therapies for AML, the disease is curable in only up to 40% of adults under 60 years of age, and older patients and those with high-risk cytogenetics have a dismal outcome, with a 2-year survival rate of <10%.1,2 Thus, new treatment options for this disease are required.
As previously described by us and others, a subset of AML cells present unique features that make them more vulnerable to impairment of mitochondrial function, such as increased mitochondrial biogenesis, decreased spare reserve capacity, and increased dependence on oxidative phosphorylation compared to normal hematopoietic progenitor cells.3-6 Based on these data, our current study focuses on inhibiting polymerase gamma (POLG), the sole mitochondrial DNA polymerase, as a new therapeutic target for this disease.
Correspondence:
AARON D. SCHIMMER aaron.schimmer@uhn.ca
Received: April 11, 2018. Accepted: December 17, 2018. Pre-published: December 20, 2018.
doi:10.3324/haematol.2018.195172
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/5/963
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2019; 104(5)
963
ARTICLE