Abstract 1906: Differential downstream effects of nicotinamide adenine dinucleotide (NAD) salvage pathway-inhibition in chronic lymphocytic leukemia (CLL) and multiple myeloma (MM).
Bibliographic record
Abstract
Abstract Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) represent the two most common hematologic malignancies in western countries. Up to date both diseases are mainly treated palliatively rather than curatively which reinforces the need for new treatment options. Targeting metabolism-associated pathways is a novel route for treatment of hematologic malignancies. Nicotinamide adenine dinucleotide (NAD) is not only a central molecule for metabolic processes such as ATP-generation, but is also involved in several other cancer-relevant events. The NAD-dependent enzyme Sirtuin 1 (Sirt1) has been described to function as an oncogene. Further, the rate-limiting enzyme for NAD-generation via salvage-pathways nicotinamide phosphoribosyltransferase (NAMPT) is upregulated in several cancers, making it an attractive metabolism-associated drug target. We used the NAMPT-inhibitor FK866 to treat the MM-cell line IM9 and the CLL-like cell lines JVM3 and Mec2 as well as primary CLL-cells. Cellular energy status was assessed by means of ATP content and functioned as a measure of viability. Sirt1 levels were assessed by immunoblotting. The MM-cell line IM9 was highly sensitive to FK866 with regard to ATP-reduction (50% reduction at 51.7nM). Also the tested CLL-like cell lines JVM3 and Mec2 were sensitive to FK866 with 50% reduction of ATP content at 76.6nM and 51.1nM, respectively. Primary CLL cells showed very heterogenous response. Some samples were highly sensitive with 50% reduction of ATP-content at 21.6nM, while others were completely resistant. We could not detect any correlation to available clinical data such as ZAP70 status or white blood cell counts. All three cell lines were positive for Sirt1. While the two CLL-like cell lines Mec2 and JVM3 showed a concentration-dependent downregulation of Sirt1 upon FK866 treatment for 72h, Sirt1 levels remained stable in the MM-cell line IM9. Primary CLL-cells showed various baseline levels of Sirt1 and a concentration-dependent downregulation upon FK866 treatment. We conclude that FK866 activity in CLL-like cell lines involves downregulation of the NAD-dependent oncogene Sirt1, while FK866 activity in the MM-cell line IM9 is Sirt1-independent. In primary CLL-cells Sirt1 baseline levels may predict responsiveness to FK866 treatment. Citation Format: Iris Gehrke, Armando Poeppl, James Johnston, Spencer B. Gibson, Versha Banerji. Differential downstream effects of nicotinamide adenine dinucleotide (NAD) salvage pathway-inhibition in chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1906. doi:10.1158/1538-7445.AM2013-1906
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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) | 0.004 | 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".