Autophagy limits proliferation and glycolytic metabolism in acute myeloid leukemia
Decreased autophagy contributes to malignancies, however it is unclear how autophagy impacts on tumour 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 population (HSPC) where transformatio...
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Published in | Cell death discovery Vol. 1; no. 1; p. 15008 |
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Main Authors | , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Springer Nature B.V
17.08.2015
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | Decreased autophagy contributes to malignancies, however it is unclear how autophagy impacts on tumour 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 population (HSPC) where transformation occurs is well characterized, and (iii) loss of the key autophagy gene
in hematopoietic stem and progenitor cells (HSPCs) leads to a lethal pre-leukemic phenotype in mice. Here we demonstrate that loss of
results in an identical HSPC phenotype as loss of
, confirming a general role for autophagy in HSPC regulation. Compared to more committed/mature hematopoietic cells, healthy human and mouse HSCs 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 tumour growth. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ASW and TR performed most experiments and contributed to manuscript writing, AS performed initial experiments on Seahorse and myeloid bias, OW and JdB transformation of MLL-ENL lines, KC and MMF Seahorse analysis, JMcG and BK proteomic analysis for metabolic proteins, SK Atg5 model breeding and analysis, PW HSPC flow cytometry and fluidigm, DP analyzed ATG5 mice for non-bone marrow-related hematopoietic defects, KP established imaging flow cytometer technique, MM set up the Atg5 model, DF performed EM, and OC and ES the histopathology, SEWJ assisted with data interpretation, supervision and manuscript writing, AKS supervised project, obtained funding, made figures and contributed to manuscript writing. |
ISSN: | 2058-7716 2058-7716 |
DOI: | 10.1038/cddiscovery.2015.8 |