Abstract 4792: Elucidating stem cell-specific metabolic pathways in normal and malignant hematopoiesis to target human acute myeloid leukemia stem cells
Notice bibliographique
Résumé
Abstract Metabolic alterations are a cancer hallmark but the metabolic requirements of hematopoietic stem cells (HSC) in general, and leukemic stem cells (LSCs) specifically are poorly understood, particularly beyond energy metabolism. By analyzing a comprehensive transcriptional roadmap of human hematopoiesis, and comparing this to a LSC signature developed from 84 primary human acute myeloid leukemia (AML) samples, we uncovered two unexpected findings: (1) several metabolic pathways, specifically in bioactive lipids, distinguish HSC from progenitors and are essential for their function; and LSC are more similar to HSC overall, but also possess specific metabolic pathways that are more comparable to those of normal progenitors. We compiled a comprehensive list of 67 genes involved in fatty acid metabolism based on literature and database information and found that 36 of these were differentially expressed between HSC and progenitors, with 24 of them higher in HSC. In particular, sphingolipid enzymes are differentially regulated throughout the hematopoietic hierarchy. Interesting, sphingosine-1-phosphate (S1P) plays a role in HSC egress and ceramide vs S1P levels serve as a rheostat to regulate growth and cell survival. We defined these 24 genes as a lipid stem signature, and find that it is enriched in the LSC gene expression profiles from our 84 primary AML cohort by GSEA analysis indicating that fatty acid metabolism is differentially regulated in LSCs and non-LSCs, as it is for HSCs vs. normal progenitors. Our signature was found to be prognostic for patient survival in a Dutch cohort of 181 cytogenetically normal AMLs. To determine if lipid metabolism plays a functional role in AML biology, we screened a fatty acid compound library using a novel AML cell line (8227) that retains hierarchical organization and assessed cell viability, phenotypic LSC content, and differentiation. We identified myriocin, which targets serine palmitoyltransferase (1st step of sphingolipid synthesis) in this screen. Myriocin decreased 8227 viability and altered differentiation in vitro and reduced leukemia burden in vivo following transplantation into NOD/SCID mice transgenic for human cytokines. Treatment of mice bearing primary AML xenografts, including those from therapy resistant and relapsed patients, with myriocin or its derivative FTY720, a S1P mimetic, resulted in reduction of leukemic engraftment. Moreover, serial transplantation of AML samples by limiting dilution showed decreased LSC frequency of FTY720- and myriocin-treated cells in secondary mice compared to vehicle-treated cells. Importantly, myriocin or FTY720 treatment do not disrupt engraftment in mice bearing normal hematopoietic grafts. Thus, sphingolipid biology in LSC is different from that of HSC, and we present a novel AML therapeutic strategy targeting bioactive sphingolipids as a means to eradicate LSC while sparing HSC. Citation Format: Stephanie Z. Xie, Elisa Laurenti, John E. Dick. Elucidating stem cell-specific metabolic pathways in normal and malignant hematopoiesis to target human acute myeloid leukemia stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4792. doi:10.1158/1538-7445.AM2014-4792
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».