Abstract 3052: NAMPT inhibition induces mitochondrial dysfunction leading to apoptosis in chronic lymphocytic leukemia cells
Bibliographic record
Abstract
Abstract We have previously shown that the NAD depletion following inhibition of NAMPT by the NA-mimetic FK866 leads to loss of mitochondrial membrane potential, depletion of cellular ATP, cytochrome C release and caspase activation in primary Chronic Lymphocytic Leukemia (CLL) cells in vitro, and that these events are coupled with an increased production of reactive oxygen species uncharacteristic of metabolic inhibition. In the present study we characterize the effect of NAD depletion on CLL mitochondria and the downstream mechanism of cell death. We profiled the mitochondrial respiration of CLL cells and control B-lymphocytes, by extracellular flux analysis, over the 48 hours following FK866 treatment and found time-dependant inhibition of respiratory capacity consistent with disruption of the electron transport chain (ETC) in CLL cells. This led to suppression of basal respiration concomitant with the rise in ROS and approximately one day before loss of cellular viability. Interestingly, Zap70-positive CLL cells exhibited increased mitochondrial respiration and respiratory capacity over Zap70-negative CLL cells, but responded similarly to NAMPT inhibition. Additionally, mitochondrial respiration was not effected by NAMPT inhibition in control B-lymphocytes. Increase autophagic flux, caspase-dependant apoptosis and mitochondrio-nuclear translocation of Apoptosis Inducing Factor (AIF) were detected by western blot. However, neither pan-caspase inhibition with Z-VAD-fmk nor inhibition of autophagy with 3-methyladenine were sufficient to prevent FK866-induced CLL cell death. We conclude that NAD depletion following inhibition of NAMPT leads to disruption of the mitochondrial ETC in CLL cells, leading to mitochondrial initiation of the intrinsic apoptosis pathway. As healthy B-lymphocytes are resistant to this NAD depletion, these downstream effects are also selective for malignant cells. We are currently working to characterize the roles of NAD and Zap70 in the regulation and function of the CLL ETC. This will not only lead to an improved understanding of CLL metabolism, but will also inform new therapeutic strategies that will effectively employ NAMPT inhibition to treat this yet-incurable disease. Citation Format: Eric DJ Bouchard, Edgard M. Mejia, Iris Gehrke, Armando G. Poeppl, Donna Hewitt, James B. Johnston, Spencer B. Gibson, Grant M. Hatch, Versha Banerji. NAMPT inhibition induces mitochondrial dysfunction leading to apoptosis in chronic lymphocytic leukemia cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3052. doi:10.1158/1538-7445.AM2015-3052
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".