Abstract A87: Targeting the mitochondrial quality control machinery in acute myeloid leukemia
Bibliographic record
Abstract
Abstract Recently, we demonstrated that a subset of AML cells and stem cells have metabolic vulnerabilities in the mitochondria and oxidative phosphorylation (OXPHOS) chain that could impact on the ability of AML and AML stem cells to handle increased electron flux in the respiratory chain (Sriskanthadevan et al., Blood, 2015). To identify additional vulnerabilities in the mitochondria of AML cells and AML stem cells, we analyzed RNA expression levels of a panel of mitochondrial quality control proteins using the nCounter Analysis System (Nanostring technologies) in bulk as well as the progenitor enriched fraction of AML patients and normal donors. Among the top hits was the mitochondrial processing peptidase (MPP) that was upregulated in AML cells and progenitors compared to normal hematopoietic cells. MPP is a metallopeptidase composed of a regulatoryα subunit and a proteolytic β subunit that cleaves presequences from several nuclear encoded and mitochondrially imported proteins. To further analyze the expression of MPP in AML, we analyzed publicly available datasets (Eppert et al., (GSE30377), Laurenti et al., (GSE42414) and Norversthen et al., (GSE24759)). GSEA (Gene Set Enrichment Analysis) on stem enriched as well as bulk AML cells demonstrated upregulation of MPPα and β as well as increased expression of the mitochondrial protein import pathway in a subset of AML cells and stem cells compared to normal hematopoietic cells and stem cells. To understand the importance of MPP in AML cells, we knocked down MPPα and β using shRNA in lentiviral vectors and confirmed target knockdown by immunoblotting. Knockdown of MPPα or β reduced the growth and viability of OCI-AML2 cells. Mechanistically, knockdown of MPP β increased mitochondrial ROS generation. Thus, the mitochondrial protein import pathway is upregulated in a subset of AML cells and stem cells. Moreover inhibition of this pathway at the level of MPPα and β is cytotoxic to AML cells and disrupts mitochondrial function. Citation Format: Danny V. Jeyaraju, Veronique Voisin, Ashwin Ramakrishnan, Rose Hurren, Neil Maclean, Marcela Gronda, Mark Minden, Gary Bader, Aaron D. Schimmer. Targeting the mitochondrial quality control machinery in acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A87.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".