Spatial metabolomics highlights metabolic reprogramming in acute myeloid leukemia mice through creatine pathway

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(10), P. 4461 - 4477

Published: July 6, 2024

Acute myeloid leukemia (AML) is recognized as an aggressive cancer that characterized by significant metabolic reprogramming. Here, we applied spatial metabolomics to achieve high-throughput, in situ identification of metabolites within the liver metastases AML mice. Alterations at metabolite and protein levels were further mapped out validated integrating untargeted proteomics. This study showed a downregulation arginine's contribution polyamine biosynthesis urea cycle, coupled with upregulation creatine metabolism. The synthetases Gatm Gamt, well transporter Slc6a8, resulted marked accumulation tumor foci. process enhances oxidative phosphorylation glycolysis cells, thereby boosting ATP production foster proliferation infiltration. Importantly, discovered inhibiting Slc6a8 can counter these detrimental effects, offering new strategy for treating targeting pathways.

Language: Английский

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Deubiquitinases in hematological malignancies

Biomarker Research, Journal Year: 2021, Volume and Issue: 9(1)

Published: Aug. 28, 2021

Abstract Deubiquitinases (DUBs) are enzymes that control the stability, interactions or localization of most cellular proteins by removing their ubiquitin modification. In recent years, some DUBs, such as USP7, USP9X and USP10, have been identified promising therapeutic targets in hematological malignancies. Importantly, potent inhibitors targeting oncogenic DUBs developed, showing inhibitory efficacy preclinical models, even undergone clinical trials. Different perform distinct function diverse malignancies, oncogenic, tumor suppressor context-dependent effects. Therefore, exploring biological roles downstream effectors will provide new insights for occurrence development We summarize involved different categories malignancies including leukemia, multiple myeloma lymphoma. also present DUB applications Together, we demonstrate potential drug

Language: Английский

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Quercetin induces autophagy-associated death in HL-60 cells through CaMKKβ/AMPK/mTOR signal pathway

Acta Biochimica et Biophysica Sinica, Journal Year: 2022, Volume and Issue: unknown

Published: Aug. 24, 2022

Acute myeloid leukemia (AML) is one of the most common malignancies hematopoietic progenitor cell in adults. Quercetin has gained recognition over years because its anti-cancer effect with minimal toxicity. Herein, we aim to investigate anti-leukemia mechanism quercetin and decipher signaling pathway HL-60 leukemic cells. We observed that induces apoptosis autophagic death, which both pathways play an important role suppressing viability Phosphorylated AMPK (p-AMPK) protein expressions are lower primary AML cells, KG-1 THP-1 cells than peripheral blood monocular After treatment, expression p-AMPK increased while p-mTOR decreased a dose-dependent manner. Mechanistically, compound C, phosphorylation inhibitor, upregulates mTOR inhibits autophagy quercetin-induced silencing CaMKKβ AMPK, resulting phosphorylation. Furthermore, Taken together, our data delineate plays by inhibiting inducing regulating activity thus playing regulation apoptosis. potential upstream molecule for AMPK/mTOR pathway, through

Language: Английский

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Molecular subtyping of acute myeloid leukemia through ferroptosis signatures predicts prognosis and deciphers the immune microenvironment

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: Aug. 24, 2023

Acute myeloid leukemia (AML) is one of the most aggressive hematological malignancies with a low 5-year survival rate and high relapse. Developing more efficient therapies an urgent need for AML treatment. Accumulating evidence showed that ferroptosis, iron-dependent form programmed cell death, closely correlated cancer initiation clinical outcome through reshaping tumor microenvironment. However, understanding heterogeneity based on extensive profiling ferroptosis signatures remains to be investigated yet. Herein, five independent transcriptomic datasets (TCGA-AML, GSE37642, GSE12417, GSE10358, GSE106291) were obtained from GEO TCGA databases. Then, we identified two ferroptosis-related molecular subtypes (C1 C2) distinct prognosis immune microenvironment (TIME) by consensus clustering. Patients in C1 subtype associated favorable outcomes increased cytotoxic infiltration, including CD8+/central memory T cells, natural killer (NK) non-regulatory CD4+ cells while showing decreased suppressive subsets such as M2 macrophages, neutrophils, monocytes. Functional enrichment analysis differentially expressed genes (DEGs) implied activation involved response, leukocyte cell-cell adhesion migration, cytokine production main biological processes. Phagosome, antigen processing presentation, cytokine-cytokine receptor interaction, B-cell receptor, chemokine major pathways. To seize landscape vs. C2 subtypes, 5-gene prognostic signature (LSP1, IL1R2, MPO, CRIP1, SLC24A3) was developed using LASSO Cox stepwise regression further validated cohorts. divided into high- low-risk groups, rates observed groups. The TIME between groups has similar scenery subtypes. Single-cell-level verified LSP1 CRIP1 upregulated exhausted CD8+ cells. Dual targeting these markers might present promising immunotherapeutic AML. In addition, potential effective chemical drugs predicted. Thus, concluded subtyping could characterize provide implications monitoring predicting novel therapies.

Language: Английский

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Engineered Cell Membrane Vesicles Loaded with Lysosomophilic Drug for Acute Myeloid Leukemia Therapy via Organ-Cell-Organelle Cascade-Targeting

Biomaterials, Journal Year: 2025, Volume and Issue: 317, P. 123091 - 123091

Published: Jan. 5, 2025

Language: Английский

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circAFF2 promotes the development of AML by binding to PML mRNA

Oncogene, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

Language: Английский

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MiR-7-5p May Inhibit AML Cell Proliferation Via SKP2, KLF4, OGT Target Genes

Clinical and Experimental Health Sciences, Journal Year: 2025, Volume and Issue: 15(1), P. 8 - 14

Published: March 23, 2025

Objective: Acute Myeloid Leukemia (AML) is distinguished by the differentiation and overgrowth of blast cells. In current study, we purposed to elucidate effect miR-7-5p on AML cellular processes expression level potential target genes. Methods: mimic was transfected into cells lipofectamine-mediated method verified qRT-PCR. The miR-7-5p's proliferation apoptosis investigated WST-8 Caspase-3 kit (respectively). miRDB, miRTarBase, Targetscan, miRWalk, https://ongene.bioinfo-minzhao.org/, http://soft.bioinfo-minzhao.org/lgl/a databases were utilized for in silico identification possible genes miR-7-5p. Relative gene via qRT-PCR technique. Results: group that with miR-7-5p, significantly decreased increased as against control group. BCL2, SKP2, OGT, KLF4 EGFR levels, which determined a result analysis methods literature search, cell lines. While OGT levels statistically no significant change detected expressions BCL2 Conclusion: may affect cancer process targeting KLF4, It very important identify validate genes, has possibility be new biomarker early diagnosis therapy AML. Therefore, our data obtained at mRNA should confirmed further studies.

Language: Английский

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Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: April 7, 2025

Abstract Background Acute myeloid leukemia (AML) is a highly aggressive cancer with 5-year survival rate of less than 35%. It characterized by significant drug resistance and abnormal energy metabolism. Mitochondrial dynamics metabolism are crucial for AML cell survival. fusion protein optic atrophy (OPA)1 upregulated in patients adverse mutations correlates poor prognosis. Method This study investigated targeting OPA1 TMQ0153, tetrahydrobenzimidazole derivative, to disrupt mitochondrial as novel therapeutic approach overcome treatment resistance. Effects TMQ0153 on mitofusin (MFN)2 levels, morphology, function cells. In this study, we examined reactive oxygen species (ROS) production, oxidative phosphorylation (OXPHOS) inhibition, membrane potential (MMP) depolarization, apoptosis. Additionally, metabolic profiling was conducted analyze changes pathways. Results significantly reduced levels disrupted the morphology increases ROS production inhibits OXPHOS, MMP caspase-dependent Metabolic reprogramming observed, shifting from respiration glycolysis impaired respiratory chain activity. Profiling revealed overall along glutathione (GSH)/oxidized (GSSG) NAD⁺/NADH redox ratios. reduces tumor volume weight MV4-11 xenografts vivo. Combination therapies other drugs leukemic burden prolonged NOD scid gamma (NSG) mice xenografted U937-luc MOLM-14-luc Conclusion targets inhibiting OPA1, inducing reprogramming, triggering apoptosis enhances efficacy existing provides promising combination that exploits vulnerability improve outcomes AML. Graphical

Language: Английский

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Combination Therapies in Drug Repurposing: Personalized Approaches to Combatting Leukaemia and Multiple Myeloma

Advances in experimental medicine and biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Emerging Bone Marrow Microenvironment-Driven Mechanisms of Drug Resistance in Acute Myeloid Leukemia: Tangle or Chance?

Cancers, Journal Year: 2021, Volume and Issue: 13(21), P. 5319 - 5319

Published: Oct. 22, 2021

Acute myeloid leukemia (AML) has been considered for a long time exclusively driven by critical mutations in hematopoietic stem cells. Recently, the contribution of further players, such as stromal and immune bone marrow (BM) microenvironment components, to AML onset progression pointed out. In particular, mesenchymal cells (MSCs) steadily remodel leukemic niche, not only favoring cell growth development but also tuning their responsiveness treatments. The list mechanisms MSCs promote drug-resistant phenotype progressively expanded. Moreover, relative proportion activation status BM may vary influencing reactivity against that, capacity stroma re-program cells, thus promoting and/or hampering therapeutic efficacy, is emerging crucial aspect biology, adding an extra layer complexity. Current treatments have mainly focused on eradicating with little consideration leukemia-damaged niche. Increasing evidence response therapy underscores need hold mutual interplay, which takes place BM. A careful dissection these interactions will help provide novel applications drugs already under experimentation open wide array opportunities new drug discovery.

Language: Английский

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