MIR125B1represses the degradation of the PML-RARA oncoprotein by an autophagy-lysosomal pathway in acute promyelocytic leukemia

Abstract

Acute promyelocytic leukemia (APL) is characterized by the t(15;17)-associated PML-RARA fusion gene. We have previously found that MIR125B1 is highly expressed in patients with APL and may be associated with disease pathogenesis; however, the mechanism by which MIR125B1 exerts its oncogenic potential has not been fully elucidated. Here, we demonstrated that MIR125B1 abundance correlates with the PML-RARA status. MIR125B1 overexpression enhanced PML-RARA expression and inhibited the ATRA-induced degradation of the PML-RARA oncoprotein. RNA-seq analysis revealed a direct link between the PML-RARA degradation pathway and MIR125B1-arrested differentiation. We further demonstrated that the MIR125B1-mediated blockade of PML-RARA proteolysis was regulated via an autophagy-lysosomal pathway, contributing to the inhibition of APL differentiation. Furthermore, we identified DRAM2 (DNA-damage regulated autophagy modulator 2), a critical regulator of autophagy, as a novel target that was at least partly responsible for the function of MIR125B1 involved in autophagy. Importantly, the knockdown phenotypes for DRAM2 are similar to the effects of overexpressing MIR125B1 as impairment of PML-RARA degradation, inhibition of autophagy, and myeloid cell differentiation arrest. These effects of MIR125B1 and its target DRAM2 were further confirmed in an APL mouse model. Thus, MIR125B1 dysregulation may interfere with the effectiveness of ATRA-mediated differentiation through an autophagy-dependent pathway, representing a novel potential APL therapeutic target.

Rationale and efficacy of proteasome inhibitor combined with arsenic trioxide in the treatment of acute promyelocytic leukemia

“…Previously reported data suggest that proteasome inhibition can induce the autophagy pathway for the degradation of ubiquitinated proteins 23, 40, 41 and that PML-RARA can be degraded by the autophagy pathway during differentiation of NB4 cells treated with ATRA or ATO. 24, 42, 43 Our data demonstrate that degradation of PML-RARA oncoprotein on combining bortezomib and ATO was mediated by autophagy that was additively induced with this combination. Reported data suggest that cargo-binding proteins such as P62, ALFY and NBR1 are involved in degrading ubiquitinated proteins.…”

Caveolin-1 contributes to realgar nanoparticle therapy in human chronic myelogenous leukemia K562 cells

“…Notably, previous studies have indicated the crucial role of autophagy in fusion oncoprotein degradation. 20 Collectively, these data suggest that autophagy may be involved in realgar NP therapy-induced degradation of Bcr-Abl fusion oncoprotein.…”

“…17 It is worth noting that autophagy participates in the therapy-induced degradation of PML-RARA oncoprotein. [18][19][20] Caveolin-1 (Cav-1), a 22-24 kDa integral membrane protein, is a principal structural component of caveolae membranes. It participates in a variety of cellular physiological and pathological processes by regulating signaling pathways.…”

Pathways related to PMA-differentiated THP1 human monocytic leukemia cells revealed by RNA-Seq

“…Transcriptional profiling has proven to be useful for determining general patterns of differential gene expression among samples [12]. Recent reports have shown that RNA-Seq is highly sensitive and can quantitatively measure gene expression in a large dynamic range of gene abundance [5,[13][14][15].…”

“…Retinoic acid (RA) treatment for acute promyelocytic leukemia has been considered a clinical success for differentiation therapy. Although several transcription factors have been identified to play important roles in leukemogenesis [3,4], the aberrant expression of oncogenes and disruption of tumor suppressor genes are most likely involved in processes responsible for blocking leukemia cell differentiation [5][6][7][8][9][10][11].…”