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Autophagy limits proliferation and glycolytic metabolism in acute myeloid leukemia

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Item Type:Article
Title:Autophagy limits proliferation and glycolytic metabolism in acute myeloid leukemia
Creators Name:Watson, A.S. and Riffelmacher, T. and Stranks, A. and Williams, O. and De Boer, J. and Cain, K. and MacFarlane, M. and McGouran, J. and Kessler, B. and Khandwala, S. and Chowdhury, O. and Puleston, D. and Phadwal, K. and Mortensen, M. and Ferguson, D. and Soilleux, E. and Woll, P. and Jacobsen, S.E.W. and Simon, A.K.
Abstract:Decreased autophagy contributes to malignancies; however, it is unclear how autophagy has an impact on tumor growth. Acute myeloid leukemia (AML) is an ideal model to address this as (i) patient samples are easily accessible, (ii) the hematopoietic stem and progenitor cells (HSPC) where transformation occurs is well characterized and (iii) loss of the key autophagy gene Atg7 in HSPCs leads to a lethal pre-leukemic phenotype in mice. Here we demonstrate that loss of Atg5 results in an identical HSPC phenotype as loss of Atg7, confirming a general role for autophagy in HSPC regulation. Compared with more committed/mature hematopoietic cells, healthy human and mouse HSPCs displayed enhanced basal autophagic flux, limiting mitochondrial damage and reactive oxygen species in this long-lived population. Taken together, with our previous findings these data are compatible with autophagy-limiting leukemic transformation. In line with this, autophagy gene losses are found within chromosomal regions that are commonly deleted in human AML. Moreover, human AML blasts showed reduced expression of autophagy genes and displayed decreased autophagic flux with accumulation of unhealthy mitochondria, indicating that deficient autophagy may be beneficial to human AML. Crucially, heterozygous loss of autophagy in an MLL–ENL model of AML led to increased proliferation in vitro, a glycolytic shift and more aggressive leukemias in vivo. With autophagy gene losses also identified in multiple other malignancies, these findings point to low autophagy, providing a general advantage for tumor growth.
Keywords:Animals, Mice
Source:Cell Death Discovery
Publisher:Nature Publishing Group
Page Range:15008
Date:17 August 2015
Official Publication:https://doi.org/10.1038/cddiscovery.2015.8
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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