4-hydroxy-2-nonenal and Leukemia--Myeloid--Acute

Metabolic alterations in cancer represent convergent effects of oncogenic mutations. We hypothesized that a metabolism-restricted genetic screen, comparing normal primary mouse hematopoietic cells and their malignant counterparts in an ex vivo system mimicking the bone marrow microenvironment, would define distinctive vulnerabilities in acute myeloid leukemia (AML). Leukemic cells, but not their normal myeloid counterparts, depended on the aldehyde dehydrogenase 3a2 (Aldh3a2) enzyme that oxidizes long-chain aliphatic aldehydes to prevent cellular oxidative damage. Aldehydes are by-products of increased oxidative phosphorylation and nucleotide synthesis in cancer and are generated from lipid peroxides underlying the non-caspase-dependent form of cell death, ferroptosis. Leukemic cell dependence on Aldh3a2 was seen across multiple mouse and human myeloid leukemias. Aldh3a2 inhibition was synthetically lethal with glutathione peroxidase-4 (GPX4) inhibition; GPX4 inhibition is a known trigger of ferroptosis that by itself minimally affects AML cells. Inhibiting Aldh3a2 provides a therapeutic opportunity and a unique synthetic lethality to exploit the distinctive metabolic state of malignant cells.

Topics: Aldehyde Oxidoreductases; Aldehydes; Animals; Carbolines; Cell Line, Tumor; Cyclohexylamines; Cytarabine; Doxorubicin; Ferroptosis; Hematopoiesis; Humans; Leukemia, Myeloid, Acute; Lipid Peroxidation; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid-Lymphoid Leukemia Protein; Neoplasm Proteins; Oleic Acid; Oncogene Proteins, Fusion; Oxidation-Reduction; Oxidative Stress; Phenylenediamines; Phospholipid Hydroperoxide Glutathione Peroxidase

Increasing evidence indicates that malignant stem cells are important for the pathogenesis of acute myelogenous leukemia (AML) and represent a reservoir of cells that drive the development of AML and relapse. Therefore, new treatment regimens are necessary to prevent relapse and improve therapeutic outcomes. Previous studies have shown that the sesquiterpene lactone, parthenolide (PTL), ablates bulk, progenitor, and stem AML cells while causing no appreciable toxicity to normal hematopoietic cells. Thus, PTL must evoke cellular responses capable of mediating AML selective cell death. Given recent advances in chemical genomics such as gene expression-based high-throughput screening (GE-HTS) and the Connectivity Map, we hypothesized that the gene expression signature resulting from treatment of primary AML with PTL could be used to search for similar signatures in publicly available gene expression profiles deposited into the Gene Expression Omnibus (GEO). We therefore devised a broad in silico screen of the GEO database using the PTL gene expression signature as a template and discovered 2 new agents, celastrol and 4-hydroxy-2-nonenal, that effectively eradicate AML at the bulk, progenitor, and stem cell level. These findings suggest the use of multicenter collections of high-throughput data to facilitate discovery of leukemia drugs and drug targets.

Topics: Aldehydes; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Cell Death; Cysteine Proteinase Inhibitors; Databases, Genetic; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Inbred NOD; Mice, SCID; Models, Genetic; Neoplastic Stem Cells; Oligonucleotide Array Sequence Analysis; Pentacyclic Triterpenes; Sesquiterpenes; Terpenes; Triterpenes; Xenograft Model Antitumor Assays