Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein

Abstract

IntroductionThe promyelocytic leukemia/retinoic acid receptor alpha (PML/ RARA) oncoprotein, which is expressed by the acute promyelocytic leukemia (APL)-specific t(15;17) chromosomal translocation, is known to inhibit granulocyte development at the promyelocytic stage of differentiation and to promote malignant transformation of hematopoietic progenitor cells mainly by acting as a repressor of gene expression. [1][2][3] All-trans retinoic acid (ATRA), the first of 2 drugs that was found to cause disease regression specifically in APL patients, interacts with the ligand binding domain present on the RARA moiety of the chimeric oncoprotein and causes both its transcriptional activation, as well as its proteolytic degradation, an effect that phenotypically leads to granulocyte differentiation of APL cells. 3,4 In later years, arsenic trioxide (ATO) also has been shown to be remarkably effective as an agent that cures APL. 4 Compared with ATRA, this drug appears to have a more limited capacity to induce differentiation and is thought to induce disease regression mainly by causing proteolytic degradation of PML/RARA. 4,5 The mechanism by which ATO causes PML/RARA proteolysis was recently shown to involve PML small ubiquitin-like modifier (SUMO)-ylation and subsequent poly-ubiquitination and proteolytic degradation of PML and PML/RARA by a protein called RNF4. 6,7 The ability of ATRA and ATO to activate disease regression through distinct molecular mechanisms that lead to PML/RARA degradation is further underscored by recent studies in which the authors showed a synergy effect of these 2 drugs both in their ability to induce clinical remission of APL patients, 8,9 as well as their capacity to cause PML/RARA degradation. 5 Thus, the ability of ATRA and ATO to activate PML/RARA degradation appears to represent a critical parameter for successful APL treatment.Two major routes for degradation of intracellular proteins exist: the ubiquitin-proteasome system (UPS) and the autophagylysosome pathway. The UPS generally is used for degradation of short-lived soluble proteins and misfolded proteins after their labeling with poly-ubiquitin chains. However, misfolded proteins that accumulate to form larger aggregates generally are poor substrates for the UPS. 10 Macro-autophagy, hereafter referred to as autophagy, involves the turnover of cytoplasmic macromolecules, protein aggregates, and defective organelles by their sequestration by double-layered membranes that form autophagosomes, which eventually fuse with lysosomes in which the sequestered contents are degraded. 11 Mice and flies lacking essential autophagy genes are characterized by increased tumorigenesis 12-14 and encompass neurodegenerative phenotypes, [15][16][17] indicating that autophagy is an important tumor-suppressive and neuroprotective mechanism.The authors of previous studies have implicated an important role of the UPS in therapy-induced degradation of PML/RARA. This role is evident from experiments showing that ATRA and ATO-induced PML/RARA degradation is b...

p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells

“…Along this line, autophagy has been shown to contribute to the degradation of PML-RARa, a leukemogenic protein, through a mechanism that involved the binding of p62/SQSTM1 to PML-RARa. 48,49 Yet, how PML-RARa is recognized and directed to autophagosomes by p62/SQSTM1 is not elucidated. Interestingly, PML-RARa is, in turn, involved in the activation of constitutive autophagy activity implying a mutual regulation between PML-RARa and autophagy pathways.…”

Cross-cancer profiling of molecular alterations within the human autophagy interaction network

“…60,61 Contradictory roles for autophagy in APL with PML-RARA fusions are described in the literature. Some studies implicate autophagy in basal and ATRA-induced degradation of PML-RARA fusions that may be beneficial for APL patients, 62 while others report constitutive autophagy activation in PML-RARA transplanted leukemic mice that supports leukemic cell growth and apoptotic resistance in vitro, following etoposide challenge. 63 It would be interesting to investigate whether high DNM1 expression increases mitophagy in M3 patients compared to other subtypes, and whether ATG4D, ULK1 and/or ATG13 are required for mitophagy in this context.…”

The role of ALFY in selective autophagy

“…Successful treatment of APL patients with the drugs all-trans retinoic acid (ATRA) or arsenic trioxide (ATO) relies on their ability to induce proteolytic degradation of PML/RARA, and we recently reported this to be autophagy dependent. 72 Thus, manipulation of autophagy or p62/ALFY levels may improve therapy for APL patients that have become resistant to ATRA/ATO.…”