Abstract 210: Targeting the mitochondrial DNA polymerase gamma with 2’3’-dideoxycytidine as a novel therapeutic strategy for acute myeloid leukemia
Bibliographic record
Abstract
Abstract A subset of AML cells display unique mitochondrial characteristics such as increased mitochondrial DNA (mtDNA), mt mass, and sensitivity to inhibition of mtDNA transcription and protein translation. Given these unique mitochondrial characteristics, we evaluated the effect of inhibiting mtDNA replication by targeting the mtDNA polymerase gamma (POLG). POLG is a nuclear-encoded gene that replicates and repairs mtDNA. POLG mRNA is increased in leukemia cell lines and a subset of AML patients. We evaluated the preclinical efficacy of targeting POLG using the nucleoside analog 2’,3’-dideoxycytidine (ddC), an FDA-approved anti-retroviral drug that cross-reacts with POLG. Treatment with ddC at 500nM depleted mtDNA by >90%, decreased mtDNA-encoded COXI and COXII proteins and basal oxygen consumption, and induced apoptosis in AML cell lines (OCI-AML2, TEX, K562). ddC further decreased cell viability in a subset of primary AML cells, while normal peripheral blood stem cells (PBSC’s) were resistant to ddC in vitro. Next, we assessed the preclinical efficacy and toxicity of ddC in an OCI-AML2 xenograft model of human AML. Treatment with 35mg/kg of i.p. ddC induced tumor regression and decreased tumor mass by >75% compared to vehicle. No toxicity was observed including changes in liver enzymes or organ histology. We also observed reductions in COXI and COXII protein in tumors but not liver excised from treated mice. We next investigated the mechanism for preferential sensitivity to ddC in AML cells. A two-fold greater decrease in mtDNA content was observed in AML cells treated with ddC compared to PBSC’s, in part explaining the heightened sensitivity. However, the increased sensitivity to ddC in AML was not due to increased mtDNA turnover as mtDNA depletion after ethidium bromide treatment was comparable between AML and PBSC’s. Therefore, we investigated the role of ddC uptake and metabolism. ddC is transported by nucleoside transporters (ENT’s, CNT’s) and activated by cytoplasmic nucleoside kinases to ddC-triphosphate (ddC-TP). Analysis of Haferlach et. al. (2010) dataset demonstrated that a subset of AML cells have higher mRNA expression of hENT2 and hCNT1, and the nucleoside diphosphate kinases NME1,2,3,5 compared to normal hematopoietic cells. Using mass spectrometry, we observed higher levels of ddC and ddCTP in sensitive AML cells compared to resistant cells. Lastly, knockdown of the deoxycytidine kinase rescued ddC cytotoxicity in TEX cells. In summary, targeting POLG with ddC displays anti-leukemic activity in both in vitro and in vivo models of AML. The preferential toxicity of ddC is due, in part, to increased rates of uptake and activation in AML along as well as their increased sensitivity to inhibition of oxidative phosphorylation. Thus, POLG inhibitors such as ddC may have clinical utility in a subset of AML. Citation Format: Sanduni Liyanage, Rose Hurren, Xiaoming Wang, Neil Maclean, Rebecca Laposa, Aaron Schimmer. Targeting the mitochondrial DNA polymerase gamma with 2’3’-dideoxycytidine as a novel therapeutic strategy for acute myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 210.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".