Targeting Folate Metabolism In Acute Myelogenous Leukemia
Notice bibliographique
Résumé
Abstract There is increasing evidence that deranged metabolism is an important mechanism of cancer pathogenesis. We conducted multiple genomic analyses of publicly available acute myelogenous leukemia (AML) data sets that revealed a critical role for one carbon and nucleotide metabolism, particularly mitochondrial, in a subset of AML samples. One carbon metabolism is a complex series of pathways involving several amino acids, the synthesis of purines, thymidylate, S-adenosylmethionine, and the support of cellular methylation reactions. SHMT2, MTHFD2, and MTHFD1L are the major enzymes functional in the one carbon folate pathway in the mitochondria. MTHFD2 is a NAD-dependent, mitochondrial methylenetetrahydrofolate dehydrogenase and cyclohydrolase, derived from a similar trifunctional cytoplasmic protein. In the mitochondria, the formyltetrahydrofolate synthetase activity is performed by MTHFD1L. We noted that these enzymes are downregulated with suppression of MYC. Gene set enrichment analysis (GSEA) of cell lines treated with JQ1, a small molecule BET bromodomain inhibitor which suppresses MYC, showed a significant enrichment in genes of the one carbon pool by folate KEGG pathway. We show that treatment of AML cells with JQ1 causes a decrease in MTHFD2 and MTHFD1L levels. This is recapitulated with knockdown of MYC with four shRNAs in multiple AML cell lines. Analysis of ENCODE ChIP-Seq data revealed MYC binding at SHMT2, MTHFD2 and MTHFD1L promoters, which we confirmed with ChIP-qPCR in human AML cell lines. Moreover, Independent component analysis (ICA) of primary AML samples in The Cancer Genome Atlas (TCGA) showed a significant correlation between high MTHFD2 and high MYC expression and a metabolic gene expression signature. MTHFD2 is differentially expressed in transformed and non-differentiated cells, and is thus an attractive drug target given its limited expression in normal tissues. Knockdown of MTHFD2 with four shRNAs in five AML cell lines caused a decrease in cell proliferation as measured by BrdU incorporation and a decrease in colony formation in methylcellulose. MTHFD2 knockdown also induced myeloid differentiation, as measured by Cd11b expression, morphologic changes and induction of a previously validated AML differentiation gene expression signature. AML cells transduced with MTHFD2-directed shRNAs demonstrated attenuated growth in an orthotopic mouse model of AML at day 15 post-injection. We next deployed a doxycycline inducible shRNA system to demonstrate that shRNAs directed against MTHFD2 cause a decrease in AML burden in mice with established disease as measured by bioluminescence with an increase in survival. Metabolite profiling is currently underway to further elucidate the metabolic consequences of MTHFD2 loss in AML. In summary, in silico analyses of primary patient AML data sets revealed a subset of AML samples enriched for a metabolic gene expression signature. We demonstrate that MYC is a regulator of the one carbon folate pathway, modulating expression of SHMT2, MTHFD2 and MTHFD1L. In vitro and in vivo data strongly supports a critical role for MTHFD2 in AML pathogenesis and its potential as a new target for AML therapy. Disclosures: No relevant conflicts of interest to declare.
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 | 0,000 | 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 ».