Autophagy a Close Relative of AML Biology

SIMPLE SUMMARY: Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Despite a high rate of complete remission following conventional chemotherapy, the prognosis remains poor due to frequent relapses caused by relapse-initiating leukemic cells (RICs), which are resistant to chemotherapies. While the development of new targeted therapies holds great promise (e.g., molecules targeting IDH1/2, FLT3, BCL2), relapses still occur. Therefore, a paramount issue in the elimination of RICs is to decipher the AML resistance mechanisms. Thus, it has been recently shown that AML cells exhibit metabolic changes in response to chemotherapy or targeted therapies. Autophagy is a major regulator of cell metabolism, involved in maintaining cancer state, metastasis, and resistance to anticancer therapy. However, whether autophagy acts as a tumor suppressor or promoter in AML is still a matter of debate. Therefore, depending on molecular AML subtypes or treatments used, a better understanding of the role of autophagy is needed to determine whether its modulation could result in a clinical benefit. ABSTRACT: Autophagy, which literally means “eat yourself”, is more than just a lysosomal degradation pathway. It is a well-known regulator of cellular metabolism and a mechanism implicated in tumor initiation/progression and therapeutic resistance in many cancers. However, whether autophagy acts as a tumor suppressor or promoter is still a matter of debate. In acute myeloid leukemia (AML), it is now proven that autophagy supports cell proliferation in vitro and leukemic progression in vivo. Mitophagy, the specific degradation of mitochondria through autophagy, was recently shown to be required for leukemic stem cell functions and survival, highlighting the prominent role of this selective autophagy in leukemia initiation and progression. Moreover, autophagy in AML sustains fatty acid oxidation through lipophagy to support mitochondrial oxidative phosphorylation (OxPHOS), a hallmark of chemotherapy-resistant cells. Nevertheless, in the context of therapy, in AML, as well as in other cancers, autophagy could be either cytoprotective or cytotoxic, depending on the drugs used. This review summarizes the recent findings that mechanistically show how autophagy favors leukemic transformation of normal hematopoietic stem cells, as well as AML progression and also recapitulates its ambivalent role in resistance to chemotherapies and targeted therapies.