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POLG inhibition promotes AML differentiation
primary AML model may reflect protection from the BM niche, or that the tested sample was resistant to alovudine. Further studies will be needed to clarify the basis for this sensitivity and resistance.
In clinical trials with patients with AIDS and HIV, alovu- dine reduced viral load but its development for HIV did not progress beyond phase II and small scale phase III tri- als.17,30,36 In these trials, alovudine was associated with dose-dependent reversible leukopenia and anemia.19 Although myelosuppression was not an acceptable toxici- ty for HIV, it may be a more manageable side effect for an anti-leukemic therapy. Moreover, our data suggest that alovudine can preferentially target AML cells over normal hematopoeitic cells. Thus, given the known toxicology and pharmacology of alovudine, along with the prior experience of its clinical use, it could potentially be rapidly repositioned for the treatment of AML.
Using a combination of pharmacological and genetic approaches, we discovered that inhibition of POLG induces the monocytic differentiation of AML cells. Thus, we identified new mechanisms by which mito- chondrial pathways control differentiation in AML and highlight alovudine as a novel potential therapeutic agent for AML. Most therapies currently in use or under investigation for AML are cytotoxic and induce cell death. A less explored therapeutic strategy is to promote the differentiation of AML cells into more mature proge- ny. Upon differentiation, the leukemic cells will cease to proliferate or die. Targeting the block in differentiation is the standard therapy for acute promyelocytic leukemia (APL)-AML.39 There is growing evidence that targeting mitochondrial pathways can impact cell fate and differ- entiation of AML beyond the subset of APL.22-24 For example, the cytosolic isocitrate dehydrogenase 1 (IDH1) and its mitochondrial homolog IDH2 encode enzymes that convert isocitrate to a-ketoglutarate (aKG), a co-fac- tor for TET2 that demethylates DNA. Mutations in IDH1 and IDH2 modify the affinity between the encoded
enzymes and their substrates, resulting in conversion of aKG to R-2-hydroxyglutarate (R-2-HG) which inhibits both TET2 and other aKG-dependent enzymes.40 The result is an increase in DNA methylation, altered gene expression, and a block in differentiation. Inhibiting mutant IDH1/2 restores normal IDH function, decreases DNA methylation, and promotes the differentiation of AML cells in vitro and in vivo.21,41
In this study, we report a new mechanism by which mitochondrial pathways control differentiation. We demonstrated that inhibition of POLG and/or reductions in levels of mitochondrial DNA that were not sufficient to impair oxidative phosphorylation led to increased mono- cytoid differentiation. Previous studies have reported that mitochondrial stress such as inhibition of the mitochondr- ial protease ClpP42,43 or oxidative stress44 can result in translocation of mitochondrial proteins to the nucleus and alter gene expression. Potentially similar mechanisms could occur upon inhibition of POLG and lead to translo- cation of proteins from the mitochondria to the nucleus, impacting gene expression to promote differentiation.
Thus, we have identified a novel mechanism by which mitochondria regulate AML fate and differentiation inde- pendently of oxidative phosphorylation. Moreover, we highlight POLG inhibitors such as alovudine as potential therapeutic agents for AML.
Acknowledgments
We thank Jill Flewelling (Princess Margaret Cancer Center) for administrative assistance.
Funding
This work was supported by Medivir AB, the Leukemia and Lymphoma Society, the Canadian Institutes of Health Research, the Princess Margaret Cancer Centre Foundation, and the Ministry of Long Term Health and Planning in the Province of Ontario. ADS holds the Barbara Baker Chair in Leukemia and Related Diseases
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