Abstract
Autophagy is one of the main cellular catabolic pathways controlling a variety of physiological processes, including those involved in self-renewal, differentiation and death. While acute promyelocytic leukemia (APL) cells manifest low levels of expression of autophagy genes associated with reduced autophagy activity, the introduction of all-trans retinoid acid (ATRA)—a differentiating agent currently used in clinical settings—restores autophagy in these cells. ATRA-induced autophagy is involved in granulocytes differentiation through a mechanism that involves among others the degradation of the PML-RARα oncoprotein. Arsenic trioxide (ATO) is another anti-cancer agent that promotes autophagy-dependent clearance of promyelocytic leukemia retinoic acid receptor alpha gene (PML-RARα) in APL cells. Hence, enhancing autophagy may have therapeutic benefits in maturation-resistant APL cells. However, the role of autophagy in response to APL therapy is not so simple, because some autophagy proteins have been shown to play a pro-survival role upon ATRA and ATO treatment, and both agents can activate ETosis, a type of cell death mediated by the release of neutrophil extracellular traps (ETs). This review highlights recent findings on the impact of autophagy on the mechanisms of action of ATRA and ATO in APL cells. We also discuss the potential role of autophagy in the development of resistance to treatment, and of differentiation syndrome in APL.
Highlights
Acute promyelocyte leukemia (APL) is mostly caused by a reciprocal chromosomal translocation between the retinoic acid receptor alpha gene (RARα) and promyelocytic leukemia (PML), and this affects a number of cellular processes, including senescence, RNA processing and apoptosis [3,4]
While autophagy is downregulated in APL cells, this process can be activated in response to all-trans retinoid acid (ATRA) and Arsenic trioxide (ATO), two agents currently used in clinical settings
A body of evidence has revealed that autophagy is involved in differentiation and degradation of the PML-RARα oncoprotein in response to both ATRA and ATO treatment
Summary
Acute myeloid leukemia (AML) encompasses a class of hematological diseases that represent an arrest of myeloid precursors at different stages of differentiation [1,2]. APL is mostly caused by a reciprocal chromosomal translocation between the retinoic acid receptor alpha gene (RARα) and promyelocytic leukemia (PML), and this affects a number of cellular processes, including senescence, RNA processing and apoptosis [3,4]. Two main mechanisms are proposed for this oncogenic function; they are based on the ability of PML-RARα to repress both the PML/p53-driven senescence program through disruption of PML nuclear bodies and the epigenetic transcription of the retinoic acid target genes [5] (Figure 1). These target genes are involved in self-renewal or differentiation following recruitment of transcription co-repressor complexes (COR). PML-RARα-driven APL development in murine tumors requires secondary oncogenic events, such as Wilms’ tumor 1 (WT1), KRAS, NRAS mutations, and fms-like tyrosine kinase 3 (FLT3) activation [6]
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