Autophagy limits proliferation and glycolytic metabolism in acute myeloid leukemia

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.

Autophagy Improves the Immunosuppression of CD4+ T Cells by Mesenchymal Stem Cells Through Transforming Growth Factor-β1

“…Previous studies have shown that autophagy limits some cells proliferation [42]. However, whether autophagy affects MSC proliferation remains controversial.…”

Mechanistic roles of autophagy in hematopoietic differentiation

“…While this suggests elevated autophagy in stem cells at a genetic level, functional evidence confirms highest autophagy in HSCs and generally declining levels as progenitors increasingly commit to lineages [24,28]. High autophagy levels in murine HSCs as measured by the autophagosome-specific dye CytoID and LC3-II colocalization with lysosomal LAMP-1+/À flux inhibitor BafilomycinA1 in GFP-LC3 transgenic mice by imaging flow cytometry was also paralleled in human HSCs [28]. It is tempting to speculate that high activity of autophagy or mitophagy is uniquely crucial in highly quiescent cells as they are unable to dilute damaged mitochondria and ROS quickly to their daughter cells.…”

Signalling mechanisms that regulate metabolic profile and autophagy of acute myeloid leukaemia cells

“…Using human AML bone marrow mononuclear cells and an AML mouse model, Watson et al54 showed that autophagy limits glycolytic metabolism in the AML context. Our data show that increased glycolytic dependence is associated with a reduced autophagy flux (Figure 3), while a diminished glycolytic metabolism, as observed in KG‐1 cells (Figure 1), was accompanied by elevated autophagy flux (Figure 3).…”