Bone Marrow Adipocyte-Derived Free Fatty Acids Induce Gene Signature Linking Transcription with Metabolic Changes That Contribute to Survival of Acute Monocytic Leukemia Cells
Notice bibliographique
Résumé
Abstract Adipocytes are the prevalent stromal cell type in adult bone marrows (BM). With increasing age, BM stroma-resident mesenchymal stem cells (MSCs), increase their capacity to differentiate into adipocytes, which leads to the progressive accumulation of fat in the BM space. It is conceivable that the increased BM adipocyte content promotes leukemogenesis and negatively affects responsiveness to chemotherapy. We previously reported that free fatty acids (FFAs) promote the metabolic shift from pyruvate oxidation to fatty acid oxidation (FAO), which causes uncoupling of mitochondrial oxidative phosphorylation and promotes leukemia cell survival (Samudio, J Clin Invest. 2010). We further demonstrated the prominent antiapoptotic effects of BM-derived adipocytes co-cultured with cells from acute monocytic leukemia (AMoL), a poor-prognosis subtype of AML (Tabe ASH. 2013). Proteomic analysis with isobaric tags for relative and absolute quantification (iTRAQ) showed upregulation of protein folding pathways which increases the expression of antiapoptotic chaperone proteins HSP70 and HSP90, of integrin-mediated cell adhesion and migration pathways and downregulation of oxidative phosphorylation along with repression of cytochrome c.Metacore gene ontology (GO) analysis identified NF-kB, c-Jun, SP1, AP-1, and HMG as the potent relevant transcription factors that closely interact with and activate chaperone proteins, chromatin, and gene transcription. In this study, we characterized a gene signature linking transcription with metabolic changes that contribute to AMoL cell survival under conditions mimicking aging BM with prevalent adipocytes. We confirmed the antiapoptotic role of FFAs produced by the primary BM MSC-derived adipocytes via pharmacologic inhibition of FAO by etomoxir (EX), which inhibits fatty acid entry into the mitochondria. EX (50mM) treatment reversed the prosurvival effects of adipocytes on serum-starved U937 monoblast cells (% Annexin V, -/+ EX: mono-culture, 30.1±9.0 / 31.5±4.6; co-culture with adipocytes, 8.9±2.1 / 29.6±9.2; P=0.02). To assess the molecular links between metabolic pathways and gene expression triggered by BM adipocytes, we performed RNA-seq transcriptome analysis with a next generation sequencer system HiSeq1500 (Illumina) using TopHat software for alignment and Cufflinks software for identifying differential gene expression. RNA-Seq detected upregulation of 21 genes in U937 cells after co-culture with BM-derived adipocytes (false discovery rate, <0.05). Specifically, 10 of these upregulated genes were significantly decreased by EX treatment, including transcription factor–activating PPARg2 promoter KLF9, co-chaperone immunophilin protein FKBP5, chemokine CXCL12 receptor CXCR4, receptor tyrosine kinase FLT3, PI3K negative regulator PIK3IP1, and immunosuppressive transcriptional regulator TSC22D3. GO pathway analysis further revealed that co-culture with adipocytes induced upregulation of antioxidant thioredoxin peroxidase activity, which was reversed by EX. Together with the iTRAQ GO results, the antioxidative chaperone proteins might play critical roles in regulation of FAO with repression of oxidative phosphorylation in AMoL cells in adipocytes abundant BM. DNA array (GeneSQUARE) analysis and quantitative RT-PCR detected upregulation of fatty acid binding protein 4 (FABP4), scavenger receptor CD36, nuclear receptor PPARG, and antiapoptotic Bcl-2 in U937 cells co-cultured with adipocytes. It is known that FFAs, the ligand of nuclear receptor PPARγ, activate PPARγ and promote FFA uptake through transcriptional induction of CD36 and FABP4 in monocytic cells. EX treatment, which blocks the entry of fatty acids into the mitochondria, induced prominent elevation of FABP4 in U937 cells co-cultured with adipocytes. These results indicate that the FABP4-mediated internalization and ligation of fatty acids to PPARγ facilitates transcriptional activation. From the transcriptome analysis and the mitochondrial uncoupling metabolic changes, we conclude that the survival of AMoL cells depends on the cooperative interactions between lipid metabolism and transcriptional activation of factors associated with chaperones, chemokines, and integrins. Strategies targeting FAO warrant further exploration in patients with monocytic leukemia, which is highly dependent on altered lipid metabolism. Disclosures No relevant conflicts of interest to declare.
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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 | 0,000 | 0,000 |
| 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) | 0,001 | 0,000 |
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 ».