The Thymidine Dideoxynucleoside Analogue, Alovudine, Inhibits the Mitochondrial DNA Polyermase, POLG, Impairs Oxidative Phosphorylation and Promotes Monocytic Differentiation in AML
Bibliographic record
Abstract
Mitochondria contain circular DNA that encodes for 13 proteins that comprise subunits of the respiratory chain and are necessary for oxidative phosphorylation. The replication of mitochondrial DNA (mt DNA) requires nucleotides from both the mitochondria and cytoplasm and is regulated by POLG (Polymerase γ), the sole mtDNA polymerase. Acute Myeloid Leukemia (AML) cells and stem cells have increased mitochondrial biogenesis and increased reliance on oxidative phosphorylation. Moreover, AML cells over-express cytoplasmic nucleoside kinases that phosphorylate nucleosides to their active forms. Alovudine (39-deoxy-39-fluorothymidine) is a dideoxynucleoside analogue of thymidine that is phosphorylated by nucleoside kinases into its active form where it selectively and potently inhibits POLG over nuclear polymerase. Therefore, we evaluated the effects of alovudine on AML cells in vitro and in vivo. OCI-AML2 and MV4-11 leukemia cells were treated with increasing concentrations of alovudine. After 6 days of treatment, alovudine decreased mtDNA by over 95% in OCI-AML2 and MV4-11 cells at 1000nM and 50nM, respectively. In contrast, cytarabine which inhibits nuclear DNA replication, did not alter levels of mtDNA. We measured levels of mt-encoded COXI and COXII proteins, subunits of respiratory chain subunit IV. Concentrations of alovudine that reduced mtDNA also reduced levels of COXI and COXII proteins in OCI-AML2 and MV4-11 cells. In contrast, alovudine did not change levels of COXIV, a subunit of respiratory chain complex IV, which is encoded by nuclear DNA, translated in the cytoplasm, and imported into the mitochondria. Consistent with reductions in respiratory chain IV subunits, alovudine decreased basal oxygen consumption in OCI-AML2 and MV4-11 cells. Finally, concentrations of alovudine that reduced mtDNA and impaired oxidative phosphorylation reduced the growth and viability of AML cell lines. We also tested the effects of alovudine on primary AML cell; In primary AML cells alovudine reduced mtDNA and decreased cell viability. Next, we examined the effects of alovudine on the growth of AML cells in vivo . SCID mice xenografted with OCI-AML2 cells were treated with alovudine (50mg/kg p.o bid 5/7 days). Alovudine decreased the growth of AML cells in vivo by 70%. At doses that decreased AML growth, no change in mouse body weight, serum chemistries, or organ histology was observed. Recent studies demonstrate that mitochondrial pathways and metabolism can regulate cell fate and differentiation. Therefore, we explored the effects of alovudine on the differentiation of OCI-AML2, MV4-11and TEX cell-lines, and the 8277 primary AML culture system. Alovudine upregulated expression of CD11b, CD14 and CD15 surface markers associated with cell differentiation. In addition, alovudine increased non-specific esterase staining and induced monocytic morphology. In summary, aluvodine is a potent inhibitor of POLG that impairs oxidative phosphorylation in AML and decreases the growth of AML cells in vitro and in vivo . We discovered that inhibition of POLG induces the monocytic differentiation of AML cells. Thus, we identified new mechanisms by which mitochondrial pathways control differentiation in AML and highlight the POLG inhibitor, aluvodine, as a novel potential therapeutic agent for this disease Disclosures Schimmer: Takeda Pharmaceuticals: Research Funding; Medivir: Research Funding; Novartis Pharmaceuticals: Honoraria. Rizoska: Medivir: Employment. Targett-Adams: Medivir: Employment. Albertella: Medivir: Employment.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".