RESUMO
Acute myeloid leukemia (AML) is an age-related disease that is highly dependent on the bone marrow (BM) microenvironment. With increasing age, tissues accumulate senescent cells, characterized by an irreversible arrest of cell proliferation and the secretion of a set of proinflammatory cytokines, chemokines, and growth factors, collectively known as the senescence-associated secretory phenotype (SASP). Here, we report that AML blasts induce a senescent phenotype in the stromal cells within the BM microenvironment and that the BM stromal cell senescence is driven by p16INK4a expression. The p16INK4a-expressing senescent stromal cells then feed back to promote AML blast survival and proliferation via the SASP. Importantly, selective elimination of p16INK4a+ senescent BM stromal cells in vivo improved the survival of mice with leukemia. Next, we find that the leukemia-driven senescent tumor microenvironment is caused by AML-induced NOX2-derived superoxide. Finally, using the p16-3MR mouse model, we show that by targeting NOX2 we reduced BM stromal cell senescence and consequently reduced AML proliferation. Together, these data identify leukemia-generated NOX2-derived superoxide as a driver of protumoral p16INK4a-dependent senescence in BM stromal cells. Our findings reveal the importance of a senescent microenvironment for the pathophysiology of leukemia. These data now open the door to investigate drugs that specifically target the "benign" senescent cells that surround and support AML.
Assuntos
Medula Óssea/patologia , Senescência Celular , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Leucemia Mieloide Aguda/patologia , Microambiente Tumoral , Animais , Medula Óssea/metabolismo , Proliferação de Células , Técnicas de Cocultura , Feminino , Humanos , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos Endogâmicos C57BL , NADPH Oxidase 2/metabolismo , Superóxidos/metabolismo , Células Tumorais CultivadasAssuntos
Leucemia/etiologia , Leucemia/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Células Estromais/metabolismo , Biomarcadores Tumorais , Respiração Celular/genética , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia/patologia , Mutação , Estadiamento de Neoplasias , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Microambiente TumoralRESUMO
Accurate radiographic measurement of acetabular cup orientation is required in order to assess susceptibility to impingement, dislocation, and edge loading wear. In this study, the accuracy and precision of a new radiographic cup orientation measurement system were assessed and compared to those of two commercially available systems. Two types of resurfacing hip prostheses and an uncemented prosthesis were assessed. Radiographic images of each prosthesis were created with the cup set at different, known angles of version and inclination in a measurement jig. The new system was the most accurate and precise and could repeatedly measure version and inclination to within a fraction of a degree. In addition it has a facility to distinguish cup retroversion from anteversion on anteroposterior radiographs.