Autophagy in the pathogenesis of myelodysplastic syndrome and acute myeloid leukemia

Abstract

Autophagy is a conserved cellular pathway responsible for the sequestration of spent organelles and protein aggregates from the cytoplasm and their delivery into lysosomes for degradation. Autophagy plays an important role in adaptation to starvation, in cell survival, immunity, development and cancer. Recent evidence in mice suggests that autophagic defects in hematopoietic stem cells (HSCs) may be implicated in leukemia. Indeed, mice lacking Atg7 in HSCs develop an atypical myeloproliferation resembling human myelodysplastic syndrome (MDS) progressing to acute myeloid leukemia (AML). Studies suggest that accumulation of damaged mitochondria and reactive oxygen species result in cell death of the majority of progenitor cells and, possibly, concomitant transformation of some surviving ones. Interestingly, bone marrow cells from MDS patients are characterized by mitochondrial abnormalities and increased cell death. A role for autophagy in the transformation to cancer has been proposed in other cancer types. This review focuses on autophagy in human MDS development and progression to AML within the context of the role of mitochondria, apoptosis and reactive oxygen species (ROS) in its pathogenesis.

Figure 1

A simplified model where an HSC or early hematopoietic precursor develops a fault in autophagy/mitophagy (1) which leads to the build up of damaged mitochondria. These in turn cause an increase in metabolic by-products, including ROS (2) which result in cellular damage including genetic instability and more mitochondrial damage. A loss of quiescence results, along with both increased apoptosis (3) and proliferation (4) in an MDS phenotype. Oncogenic mutations may result in transformation and AML (5).