A mitochondrial drug to treat AML

Paolo Pinton

In this issue of Blood, Liyanage et al demonstrate that acute myeloid leukemia (AML) cells exhibit increased mitochondrial DNA (mtDNA) content and that the 2′,3′-dideoxycytidine (ddC; an inhibitor of mtDNA biosynthesis already used in clinic) selectively kills leukemia cells.1

A cell belonging to a subtype of AML clusters which is characterized by high cytoplasmic nucleoside kinase activity (deoxycytidine kinase [DCK], CMPK1, and NME) is depicted. As a consequence, a large nucleoside pool is imported in mitochondria via the SLC25A33/36 and SLC29A3 import carriers as indicated by the green boxes on the left of the mitochondrial membrane. This pool favors mtDNA biosynthesis, oxidative phosphorylation (OXPHOS), and increased oxygen consumption rate (OCR). ddC treatment minimizes mtDNA content upon its activation in 2′,3′-dideoxycytidine triphosphate (ddCTP) (on the right) and import into mitochondria. This treatment allows the tumor regression in a mouse model. POLG2, DNA polymerase γ2.

AML is a blood cancer wherein the uncontrolled proliferation of immature myeloid cells leads to bone marrow failure. AML is now cured in only 30% of young patients, with a worse prognosis in older patients.2 One of the problems in improving therapy in AML is that there are multiple types of AML that differ in genetic abnormalities, immunophenotype, and clinical features.3

The current study by Liyanage and coworkers focused on a subset of primary human AML cases characterized by increased mitochondrial biogenesis and reliance on oxidative phosphorylation in AML cells compared with normal progenitors. These features were linked to increased mtDNA biosynthesis. It is widely known that mtDNA content and its replication takes advantage of mitochondrial nucleotide pools; however, the large mtDNA content found in this AML subset requires the support of the nucleotides imported from the cytosolic compartment. By Affymetrix gene expression analysis, the authors observed an upregulation of the genes involved in mtDNA biosynthesis in a subset of AML samples that were not associated with known cytogenetic abnormalities. Moreover, the pattern was upregulated in leukemia cell lines but not in other cancer types. As increased mtDNA biosynthesis needs a massive infusion of nucleotides, the authors suggest that this could be accomplished by import of cytoplasmic nucleotides. Mitochondrial nucleotide transporters and cytoplasmic nucleoside kinase activity were investigated by immunoblotting and mass-spectrometry approaches. The analysis revealed increased nucleotide import from the cytoplasm due to SLC25A33, SLC25A36, and SLC29A3 activity and parallel augmented cytoplasmic nucleoside activity in AML cells compared with normal progenitors. The major question arising from these novel findings is how to use the discrepancies between AML and normal cells to selectively induce cell death (see figure).

In the last 10 years, there have only been refinements in AML chemotherapy.4 The work of Liyanage et al has potential impact for new therapeutic approaches.

ddC is a nucleoside analog made by replacing the hydroxyl group in position 3′ of a pyrimidine. ddC is activated in ddCTP by cytoplasmic nucleoside kinases and imported into mitochondria where it is a selective inhibitor of mtDNA polymerase. The activation of ddC in ddCTP was greater in AML cells compared with control. ddC treatment was more effective in the inhibition of mtDNA content in AML cells leading to a decrease of the mtDNA-encoded COX I and COX II proteins resulting in alteration of mitochondrial morphology and activity in AML cells.

Although the clinical use of ddC is already known, these findings provide a molecular basis for future clinical studies. Since its approval in 1992, ddC has been used alone or in combination for the treatment of AIDS as a reverse transcriptase inhibitor5; however, severe adverse events were seen in a significant number of patients. Previous studies have shown an amplification of the mtDNA in AML6 and suggest that this could be a therapeutic target.7 Here, the use of ddC in an AML mouse model was encouraging, not only for the greater tumor regression obtained using ddC treatment (from 75% to a 90% of the total mass), but also for its potential effects on the leukemic stem cells and for the minimal cytotoxic effects in normal progenitor cells. Importantly, treatment with ddC did not affect normal mouse hematopoiesis, body weight, or behavior. Although this study has remarkable clinical implications, some issues have to be addressed. It would be interesting to investigate a putative ddC-induced resistance in the treatment of AML due to the onset of mutations in mtDNA.


  • Conflict-of-interest disclosure: The author declares no competing financial interests.


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