RESUMO
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.
Assuntos
Aldeído Oxirredutases/fisiologia , Carbolinas/farmacologia , Cicloexilaminas/farmacologia , Ferroptose/efeitos dos fármacos , Hematopoese/fisiologia , Leucemia Mieloide Aguda/enzimologia , Proteínas de Neoplasias/fisiologia , Fenilenodiaminas/farmacologia , Aldeído Oxirredutases/genética , Aldeídos/farmacologia , Animais , Linhagem Celular Tumoral , Citarabina/administração & dosagem , Doxorrubicina/administração & dosagem , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Peroxidação de Lipídeos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína de Leucina Linfoide-Mieloide/fisiologia , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genética , Ácido Oleico/farmacologia , Proteínas de Fusão Oncogênica/fisiologia , Oxirredução , Estresse Oxidativo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/antagonistas & inibidores , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/fisiologiaRESUMO
Distinctive metabolism associated with particular cell states is increasingly being defined in normal and malignant cells. Ito et al. (2012) now show that fatty acid oxidation is associated with hematopoietic stem cells and determines whether they undergo symmetric or asymmetric cell division, driving a fundamental property of the stem cell state.