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Innovations & Thérapeutiques en Oncologie

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Therapeutic targeting of autophagy in malignant haemopathies Volume 4, issue 5-6, September-December 2018

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Authors
Université Côte d’Azur
Centre méditerranéen de médecine moléculaire
Bâtiment ARCHIMED
151, route de Saint-Antoine de Ginestière
BP 23194, 06204 Nice Cedex 2
France
* Tirés à part
  • Key words: autophagy, chaperone-mediated autophagy, malignant haemopathies, resistance to therapies
  • DOI : 10.1684/ito.2018.0141
  • Page(s) : 241-53
  • Published in: 2018

The term ‘autophagy’ refers to a set of catabolic processes which have the common characteristic of leading to degradation of macromolecules and organelles by the lysosome. Macroautophagy (or autophagy) is initiated by nucleation of a phagophore, derived from intracellular membranes. Following expansion, the ends of the phagophore join to form an autophagosome, in which the material to be degraded is sequestered. Material degradation takes place following fusion with the lysosome, which delivers the enzymatic activities necessary for this catabolic process. The degraded material is eliminated or generates simple molecules that can be reused by the cell in adverse conditions. Chaperone-mediated autophagy (CMA) is a highly selective form of autophagy that allows the degradation of cytosolic proteins endowed with a KFERQ-like peptide sequence. The protein substrate is first recognised by a molecular chaperone, HSC70, and delivered to the lysosomal associated membrane receptor (LAMP2A), which serves as a transporter for the linearised protein substrate. Once translocated inside the lumen of the lysosome, the protein substrate is degraded. These two forms of autophagy play a key role in the physiological differentiation of haematopoietic cells, as well as during leukemogenesis. Autophagy and CMA may also exert tumour promoter or suppressive functions depending on the cellular context. Most cancer treatments currently used are thought to affect both processes. In this context, modulation of autophagy has become a pertinent therapeutic option, notably for haematopoietic malignancies. However, given the complexity of autophagy regulation, it is crucial to define, for each subset of haematopoietic malignancy, where, when and how targeting autophagy will be the most efficient. In this article, we address the role of autophagy in haematopoietic malignancies and describe ongoing clinical trials in which modulators of autophagy are used to improve the available therapeutic armamentarium.