Current Outlook on Autophagy in Human Leukemia: Foe in Cancer Stem Cells and Drug Resistance, Friend in New Therapeutic Interventions

Abstract

Autophagy is an evolutionarily conserved cellular recycling process in cell homeostasis and stress adaptation. It confers protection and promotes survival in response to metabolic/environmental stress, and is upregulated in response to nutrient deprivation, hypoxia, and chemotherapies. Autophagy is also known to sustain malignant cell growth and contributes to cancer stem cell survival when challenged by cytotoxic and/or targeted therapies, a potential mechanism of disease persistence and drug resistance that has gathered momentum. However, different types of human leukemia utilize autophagy in complex, context-specific manners, and the molecular and cellular mechanisms underlying this process involve multiple protein networks that will be discussed in this review. There is mounting preclinical evidence that targeting autophagy can enhance the efficacy of cancer therapies. Chloroquine and other lysosomal inhibitors have spurred initiation of clinical trials and demonstrated that inhibition of autophagy restores chemosensitivity of anticancer drugs, but with limited autophagy-dependent effects. Intriguingly, several autophagy-specific inhibitors, with better therapeutic indexes and lower toxicity, have been developed. Promising preclinical studies with novel combination approaches as well as potential challenges to effectively eradicate drug-resistant cells, particularly cancer stem cells, in human leukemia are also detailed in this review.

Proteome and Phosphoproteome Changes Associated with Prognosis in Acute Myeloid Leukemia

“…The V-ATPase complex can modulate several intracellular signaling pathways with importance in AML (such as PI3K-mTOR [83,84], NOTCH1 [85] and WNT [86]) by controlling acidification of intracellular compartments. V-ATPase is also important for autophagy [87]. Two previous studies have described an association between low expression at the mRNA level of single autophagic regulators and an adverse prognosis.…”

Assessing Autophagy in Archived Tissue or How to Capture Autophagic Flux from a Tissue Snapshot

“…Interestingly, using an MLL-Af9 leukemia model, Liu et al reported that while macroautophagic activity is key for the disease development, it is dispensable for the maintenance of leukemia [103]. Therefore, although autophagy is critical in the maintenance of hematopoietic stem cells (HSCs), it plays context-dependent roles in leukemia initiation and progression, suggesting a highly complex role for autophagy in leukemic transformation and leukemic stem cells properties in AML (reviewed in [104]). To further complicate this scenario, autophagy is also established as one of the resistance mechanisms of leukemic cells to chemotherapy [94,95].…”

Retinoic Acid Receptors in Acute Myeloid Leukemia Therapy

“…The autophagosome is a bi-membrane vesicle that envelops the cellular content targeted for degradation. This highly conserved mechanism protects cells from metabolic/environmental stress (e.g., nutrient deprivation, hypoxia, and chemotherapies) and controls cell self-renewal, differentiation, and death [110]. Autophagy is crucial for the maintenance of HSCs.…”