LSD1 inhibition enhances venetoclax efficacy in Acute Myeloid Leukemia via metabolic rewiring
Bibliographic record
Abstract
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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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) | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".