Induction of autophagy is a key component of all-trans-retinoic acid-induced differentiation in leukemia cells and a potential target for pharmacologic modulation

Abstract

Acute myeloid leukemia (AML) is characterized by the accumulation of immature blood cell precursors in the bone marrow. Pharmacologically overcoming the differentiation block in this condition is an attractive therapeutic avenue, which has only achieved success in a subtype of AML, acute promyelocytic leukemia (APL). Attempts to emulate this success in other AML subtypes have thus far been unsuccessful. Autophagy is a conserved protein degradation pathway with important roles in mammalian cell differentiation, particularly within the hematopoietic system. In this study we demonstrate the functional importance of autophagy in APL cell differentiation. We show that autophagy is increased during ATRA-induced granulocytic differentiation of the APL cell line NB4, and that this is associated with increased expression of LC3-II and GATE-16 proteins involved in autophagosome formation. Autophagy inhibition, using either drugs (chloroquine/3-methyladenine) or short-hairpin (sh)RNA targeting the essential autophagy gene ATG7, attenuates myeloid differentiation. Importantly, we show that enhancing autophagy promotes ATRA-induced granulocytic differentiation of an ATRA-resistant derivative of the non-APL AML HL60 cell line (HL60-Diff-R). These data support the development of strategies to stimulate autophagy as a novel approach to promote differentiation in AML.

Autophagy and Ubiquitin-Mediated Proteolytic Degradation of PML/Rarα Fusion Protein in Matrine-Induced Differentiation Sensitivity Recovery of ATRA-Resistant APL (NB4-LR1) Cells: in Vitro and in Vivo Studies

“…The most efficient agents, ATRA and ATO, both directly target PML/RARα-mediated transcriptional repression and protein stability [14], contributing to a significant decrease in the expression level of fusion protein. The induction of autophagy is a key component of ATRA-induced differentiation in APL, and during the treatment of ATRA [15], the UPP is also activated [16]. The mechanism of ATRA resistance in APL is still not fully clarified.…”

“…Autophagy is increased during ATRA-induced granulocytic differentiation of NB4 and it is associated with the increased expression of LC3II and GATE-16 proteins involved in autophagosome formation. Autophagy inhibition, using either drugs or short-hairpin RNA targeting the essential autophagy gene ATG7, attenuated myeloid differentiation [15]. The inhibition of autophagy-related genes such as Atg1, Atg5, and PI3KC3 and the knockdown of p62/SQSTM1 also blocked the degradation of PML-RARα [24].…”

Extracellular DNA traps released by acute promyelocytic leukemia cells through autophagy

“…44, 45, 46 Recent studies demonstrate that parts of the nucleus can be specifically degraded by an autophagic process termed nucleophagy. 47 In this study, we find that in the early stage of ETosis, nuclear material are sequestered and packed in vesicles.…”

Tazarotene-Induced Gene 1 Enhanced Cervical CellAutophagy through Transmembrane Protein 192

“…TIG1 is a retinoid-inducible protein (Nagpal et al, 1996), and previous studies have confirmed that ATRA can induce the activation of autophagy in leukemia cells (Anguiano et al, 2013; Orfali et al, 2015; Rajawat et al, 2010). To determine whether TIG1 or TMEM192 contributes to the ATRA-mediated activation of autophagy, we examined the effects of TIG1 or TMEM192 silencing on the production of LC3B and Beclin-1 in ATRA-treated cells.…”

“…Autophagy regulates myeloid cell differentiation, and autophagy is increased during ATRA-induced granulocytic differentiation of acute promyelocytic leukemia cells (Orfali et al, 2015; Wang et al, 2011). How autophagy is induced by ATRA is not yet known, but our results revealed that silencing of either TIG1 or TMEM192 alleviated ATRA-upregulated autophagy.…”