LSD1 inhibition enhances venetoclax efficacy in Acute Myeloid Leukemia via metabolic rewiring
Notice bibliographique
Résumé
Abstract Introduction Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor outcomes. Venetoclax, a BCL2 inhibitor, improves response in older AML patients by targeting leukemic stem cell (LSC) metabolism, but resistance limits its efficacy. Lysine-specific demethylase 1 (LSD1) inhibition has shown promise in AML by promoting differentiation and reducing LSCs. We investigated whether LSD1 inhibitor bomedemstat could enhance venetoclax efficacy in AML. Methods We assessed the cytocidal effects of venetoclax and bomedemstat, alone and in combination, in Hoxa9/Meis1- and MN1-transformed murine myeloid cell lines, 7 human AML cell lines, 26 primary AML samples (across risk groups), and 3 venetoclax-refractory AML samples. In vivo efficacy was studied in two patient-derived xenograft (PDX) models. Gene expression and epigenetic changes were analyzed using bulk RNA sequencing and 10x Chromium Multiome single-cell assays in MOLM-13 cells. Metabolic changes were examined using Seahorse® extracellular flux analyzer and NMR spectrometry. Results Venetoclax alone showed variable IC50 values (6.37 nM–26.3 µM) among primary AML samples, with greater sensitivity in IDH2, WT1, FLT3, and NPM1 mutant samples. Bomedemstat also showed sample-dependent sensitivity (IC50 12.8 nM–110 µM), particularly in IDH2, FLT3, NPM1, and DNMT3A-mutant samples. Co-treatment resulted in synergistic cytotoxicity in 19 of 26 samples, independent of genotype, with synergy correlating with bomedemstat sensitivity (ρ = 0.52, P = 0.0061). Synergism was also observed in two venetoclax-refractory AML samples and one transformed MPN sample. To assess in vivo efficacy, we tested the drug combination in PDX models using two primary AML samples, analyzing mice immediately post-treatment and two weeks later. In the first model (monosomy 7), co-treatment significantly reduced human CD45+ cells in bone marrow vs. vehicle at both timepoints (P = 0.0006 and P = 0.004). Similarly, in second model (NPM1-mutated, FLT3-ITD), leukemic burden was significantly reduced at both timepoints (P = 0.02 and P = 0.017), indicating sustained anti-leukemic effects. The combination also synergistically reduced cell proliferation in murine MN1 cells and human AML cell lines including MOLM-13, MV4-11, Kasumi-1, and KG1a, which served as model systems for mechanistic studies. In MOLM-13 cells, 1 µM bomedemstat treatment enhanced venetoclax-induced apoptosis, increasing Annexin V+ cells from 19.8 ± 0.8% with 100 nM venetoclax alone to 46.6 ± 4.7%. A 5 x 5 dose-response matrix confirmed this synergistic apoptosis effect. RNA sequencing analysis revealed that bomedemstat upregulated myeloid differentiation genes and downregulated glycolysis-related gene expression. Seahorse® analysis showed that bomedemstat treatment led to a dose-dependent reduction in glycolysis (reduced proton efflux rate, PER) and an increase in oxygen consumption rate (OCR)/PER ratio, indicating a metabolic shift toward oxidative phosphorylation (OxPhos). In contrast, venetoclax suppressed OxPhos (reduced OCR and OCR/PER). Co-treatment inhibited both pathways more strongly, suggesting broad suppression of cellular energy metabolism. NMR-based metabolomics confirmed reduced metabolite abundance across multiple metabolic pathways upon combination treatment. These data suggest bomedemstat primes AML cells for venetoclax by rewiring metabolism toward mitochondrial dependence. Supporting this, combining bomedemstat with OxPhos inhibitors (IACS-010759, rotenone, antimycin, oligomycin) synergistically reduced cell proliferation, and Rho-zero MOLM-13 cells, lacking mitochondrial DNA, were more sensitive to bomedemstat than wild-type cells. Consistent with its metabolic effects, bomedemstat increased expression (P = 0.0002) and activation (P = 0.02) of the energy stress sensor AMPK, as shown by western blotting. AMPK activation suppresses anabolic processes such as lipid biosynthesis to restore energy balance. Accordingly, gene set enrichment analysis revealed significant downregulation of lipid biosynthesis pathways following bomedemstat treatment in MOLM-13 cells.Conclusion: Bomedemstat and venetoclax co-treatment showed synergistic anti-leukemic effects in AML models in vitro and in vivo. Our findings suggest that LSD1 inhibition primes AML cells to venetoclax via differentiation-induced metabolic rewiring and activation of AMPK-mediated stress responses, providing the basis for a planned clinical trial.
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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) | 0,002 | 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 ».