RESUMO
The chromatin-associated AAA+ ATPases Tip48 and Tip49 are the core components of various complexes implicated in diverse nuclear events such as DNA repair and gene regulation. Although they are frequently overexpressed in many human cancers, their functional significance remains unclear. Here, we show that loss of Tip49 triggered p53-dependent apoptosis and inhibited leukemia development in vivo. To examine the impact of chemical inhibition of this complex on leukemia, we have developed the novel compound DS-4950, which interferes with the ATPase activity of the Tip48/49. Administration of DS-4950 was well-tolerated in healthy mice, and the drug effectively reduced tumor burden and improved survival. We also provide evidence that the dependency on Tip48/49 is widely conserved in non-hematologic malignancies with wild type p53. These results demonstrated that the Tip48/49 ATPases are functionally necessary and therapeutically targetable for the treatment of human cancers.
Assuntos
DNA Helicases , Leucemia Mieloide Aguda , Humanos , Camundongos , Animais , DNA Helicases/genética , Proteínas de Transporte/genética , Proteína Supressora de Tumor p53/genética , Adenosina Trifosfatases/genética , ATPases Associadas a Diversas Atividades Celulares/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genéticaRESUMO
Eradication of chemotherapy-resistant leukemia stem cells is expected to improve treatment outcomes in patients with acute myelogenous leukemia (AML). In a mouse model of AML expressing the MOZ-TIF2 fusion, we found that Ring1A and Ring1B, components of Polycomb repressive complex 1, play crucial roles in maintaining AML stem cells. Deletion of Ring1A and Ring1B (Ring1A/B) from MOZ-TIF2 AML cells diminished self-renewal capacity and induced the expression of numerous genes, including Glis2 Overexpression of Glis2 caused MOZ-TIF2 AML cells to differentiate into mature cells, whereas Glis2 knockdown in Ring1A/B-deficient MOZ-TIF2 cells inhibited differentiation. Thus, Ring1A/B regulate and maintain AML stem cells in part by repressing Glis2 expression, which promotes their differentiation. These findings provide new insights into the mechanism of AML stem cell homeostasis and reveal novel targets for cancer stem cell therapy.
Assuntos
Regulação Leucêmica da Expressão Gênica , Histona Acetiltransferases/biossíntese , Fatores de Transcrição Kruppel-Like/biossíntese , Leucemia Mieloide Aguda/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Coativador 2 de Receptor Nuclear/biossíntese , Proteínas de Fusão Oncogênica/biossíntese , Complexo Repressor Polycomb 1/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Diferenciação Celular , Histona Acetiltransferases/genética , Fatores de Transcrição Kruppel-Like/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Coativador 2 de Receptor Nuclear/genética , Proteínas de Fusão Oncogênica/genética , Complexo Repressor Polycomb 1/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
Polycomb group (PcG) proteins are epigenetic regulatory factors that maintain the repression of target gene expression through histone modification. PcG proteins control the repression of genes that regulate differentiation and the cell cycle in the maintenance of hematopoietic stem cells (HSC). Moreover, abnormalities in expression level and mutations in PcG genes have been reported in various types of cancer, including hematological malignancies. In this review, we present an overview of the roles of PcG proteins in HSC and various types of hematological malignancies.
