Abstract 446: LONP1 inhibition induces mitochondrial proteotoxic stress and is cytotoxic to acute myeloid leukemia cells
Bibliographic record
Abstract
Abstract Acute myeloid leukemia (AML) is a hematological malignancy characterized by the uncontrolled proliferation of abnormal myeloid precursors that fail to fully differentiate, resulting in the accumulation of malignant leukemic cells. High rates of nuclear-encoded protein synthesis, supporting increased proliferation rates, render leukemic cells reliant on increased proteolytic systems to clear misfolded proteins. Compared to non-transformed blood cells, AML cells and stem cells exhibit a unique metabolic phenotype characterized by increased mitochondrial mass and greater reliance on oxidative metabolism for survival and proliferation. To identify novel biological vulnerabilities in the mitochondrial proteome, we analyzed the DepMap (depmap.org) for essential mitochondrial genes in AML. Through this analysis, we identified the mitochondrial protease LONP1 as essential for a subset of AML and in the top 10% of essential genes for this disease. LONP1 is a nuclear-encoded AAA+ serine protease that resides in the mitochondrial matrix and maintains the mitochondrial proteome, mainly via the clearance of misfolded, unassembled or oxidatively-damaged proteins. However, its importance and function in AML has not been previously reported. Compared to normal hematopoietic cells, LONP1 mRNA was overexpressed in AML across three publicly available datasets while LONP1 protein was increased >2 fold in tested AML primary samples (N=16). Using shRNA and CRISPR gRNA, LONP1 knockdown and knockout reduced the growth and viability of OCI-AML2, OCI-M2, and NB4 cells. Mechanistically, genetic knockdown or knockout of LONP1 increased levels of insoluble, aggregated mitochondrial proteins including ClpP, TUFM, and NDUFA9 as measured by immunoblotting of soluble and insoluble protein fractions as well as by the fluorescence of the protein aggregation dye PROTEOSTAT by confocal microscopy. The accumulation of insoluble mitochondrial protein aggregates through LONP1 inhibition exploits an increased reliance on chaperone and protease systems due to abnormally high protein synthesis. This novel therapeutic avenue targets a unique metabolic vulnerability to eliminate AML cells. Citation Format: Matthew Tcheng. LONP1 inhibition induces mitochondrial proteotoxic stress and is cytotoxic to acute myeloid leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 446.
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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) | 0.001 | 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) | 0.005 | 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".