The role that autophagy pathways play in cancer, as a suppressor of tumor development or a driver of oncogenic transformation, remains a topic of debate and controversy. In some instances, there are indicative links between mutations that drive cancers and regulation of autophagy. For example, activation of the PI3K/AKT/mTOR pathway is well recognized in many different tumor types—a result often of activating mutations in PI3K, AKT or mTOR, or loss of function mutations in the negative regulators, PTEN, TSC1 and TSC2. PI3K signaling is also activated by a number of receptor tyrosine kinases, including EGFR, HER2, c-Kit and PDGFRA. There is little doubt that PI3K pathway activation suppresses autophagy. However, activation of PI3K pathways has other direct tumor-promoting capabilities, such as promoting cell growth, translation and proliferation. Thus while the frequency of activation of PI3K/AKT/mTOR signaling in cancers raises the very distinct possibility that repression of autophagic flux contributes to oncogenic transformation, it does not prove it.

Watson and colleagues noted that haematopoietic stem and progenitor cells have higher autophagic flux than mature hematopoietic cells, whilst AML blasts tend to have reduced flux. This, together with the fact that a number of autophagic genes exist (along, of course, with many other genes), in genomic regions that are subject to copy-number loss in AML, hint at an association between diminished autophagy and the development of AML.

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