![]() ![]() 5-7 Moreover, the profoundly hypoxic bone marrow niche is believed to induce autophagy in AML cells. 4 Indeed, chemotherapy can upregulate autophagy in tumors, which in turn can protect transformed cells from organelle damage and nutrient deprivation. Thus, the inhibition of Atg7 appears to be a valid strategy to enhance chemosensitivity, and it could indeed improve outcomes in AML therapy.Īutophagy is an evolutionally conserved pathway that is used by cells to recycle damaged cellular components as a mechanism of adaption to adverse environmental stimuli, including that triggered by exposure to chemotherapeutic agents. Finally, in a mouse model of human leukemia, Atg7 knockdown extended overall survival after chemotherapy. Mechanistic studies revealed that Atg7 knockdown induced a proapoptotic phenotype in AML cells, which was manifested by an increased NOXA expression at the transcriptional level. These findings strongly suggest that Atg7, and likely microenvironment autophagy in general, plays an important role in AML chemoresistance. This effect was further enhanced by concomitant knockdown of Atg7 in both AML and stromal cells. ![]() Interestingly, coculture of AML cells with stromal cells increased autophagy and chemoresistance in the AML cells exposed to chemotherapeutic agents, and this was reversed following Atg7 knockdown. Knockdown of Atg7 in AML cells using short hairpin RNA markedly increased apoptosis and DNA damage following treatment with cytarabine and idarubicin. Reverse phase protein array suggested that high expression of the essential autophagy-related protein, Atg7, was associated with shorter remission in newly diagnosed acute myeloid leukemia (AML) patient samples, indicating a role in chemoresistance. Autophagy is a cellular adaptive mechanism to stress, including that induced by chemotherapeutic agents. ![]()
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