title: Autophagy limits proliferation and glycolytic metabolism in acute myeloid leukemia.
abstract: 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 geneAtg7in hematopoietic stem and progenitor cells (HSPCs) leads to a lethal pre-leukemic phenotype in mice. Here we demonstrate that loss ofAtg5results in an identical HSPC phenotype as loss ofAtg7, 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.
authors.affiliation: Translational Immunology Lab, BRC- NIHR, John Radcliffe Hospital, Experimental Medicine, Nuffield Department of Medicine, Oxford OX3 9DU, UK ; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Watson
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Riffelmacher
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Stranks
authors.affiliation: Molecular Haematology and Cancer Biology Unit, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Owen
authors.initials: O
authors.lastname: Williams
authors.affiliation: Molecular Haematology and Cancer Biology Unit, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Jasper
authors.initials: J
authors.lastname: De Boer
authors.affiliation: MRC Toxicology Unit, Hodgkin Building, University of Leicester, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Kelvin
authors.initials: K
authors.lastname: Cain
authors.affiliation: MRC Toxicology Unit, Hodgkin Building, University of Leicester, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Marion
authors.initials: M
authors.lastname: MacFarlane
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: McGouran
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Kessler
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Shivani
authors.initials: S
authors.lastname: Khandwala
authors.affiliation: Haematopoietic Stem Cell Biology, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Onima
authors.initials: O
authors.lastname: Chowdhury
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Puleston
authors.affiliation: Translational Immunology Lab, BRC- NIHR, John Radcliffe Hospital, Experimental Medicine, Nuffield Department of Medicine, Oxford OX3 9DU, UK.
authors.forename: Kanchan
authors.initials: K
authors.lastname: Phadwal
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Monika
authors.initials: M
authors.lastname: Mortensen
authors.affiliation: Nuffield Department of Clinical and Laboratory Sciences, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: David
authors.initials: D
authors.lastname: Ferguson
authors.affiliation: Nuffield Department of Clinical and Laboratory Sciences, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Soilleux
authors.affiliation: Haematopoietic Stem Cell Biology, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Petter
authors.initials: P
authors.lastname: Woll
authors.affiliation: Haematopoietic Stem Cell Biology, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Sten Eirik W
authors.initials: SE
authors.lastname: Jacobsen
authors.affiliation: Translational Immunology Lab, BRC- NIHR, John Radcliffe Hospital, Experimental Medicine, Nuffield Department of Medicine, Oxford OX3 9DU, UK ; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Anna Katharina
authors.initials: AK
authors.lastname: Simon
keywords: Acute Myeloid Leukemia (AML); Autophagy; Cancer; Glycolysis; Hematopoiesis; Hematopoietic Stem Cell; Metabolism; Myeloid cells