Targeting autophagy to fight hematopoietic malignancies.
Macroautophagy, referred hereafter to as autophagy is an evolutionary conserved catabolic process for the degradation and recycling of macromolecules, bulk cytoplasm and dammaged organelles. Autophagy is activated under stress conditions induced by nutrient deprivation, hypoxia and drug treatments. Morphologically, autophagic cells are characterized by the accumulation of double membrane cytoplasmic vesicules called autophagosomes that surrounds cytoplasmic proteins and/or organelles. Autophagosomes next fuse with lysosomes to generate autolysosomes, the structures in which the retained constituents are digested before recycling into the cytoplasm. In this context, autophagy promotes cell survival under adverse conditions. In contrast, under certain circumstances autophagic cells may engage a specific mode of cell death called type II cell death or autophagic cell death (ACD). Considering the strategic positionnement of this process at the crossroads of cell death and survival, it is not surprising that defects in autophagy have been linked to a plethora of human diseases, including hematopoietic malignancies. Finally, autophagy induction is repressed by the mammalian target of rapamycin complex 1 (mTORC1) and favored by the adenosine-monophosphate activated-protein kinase (AMPK). In the present review, we focus on the functions of autophagy in normal and malignant hematopoiesis and discuss the opportunity to target the AMPK/mTOR pathways as a new therapeutic strategy to fight hematopoietic malignancies with a special emphasis on Chronic Myelogenous Leukemia (CML).
Puissant
Alexandre
A
INSERM U895, Batiment Universitaire ARCHIMED, CHU Hopital de l'Archet, Nice Cedex, France.
Robert
Guillaume
G
Auberger
Patrick
P
D001343:Autophagy; D002454:Cell Differentiation; D019337:Hematologic Neoplasms / Q000473:pathology / Q000628:therapy*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology / Q000628:therapy; D015470:Leukemia, Myeloid, Acute / Q000473:pathology / Q000628:therapy; D009101:Multiple Myeloma / Q000473:pathology / Q000628:therapy; D009190:Myelodysplastic Syndromes / Q000473:pathology / Q000628:therapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology / Q000628:therapy; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D058570:TOR Serine-Threonine Kinases