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Clinical significance of increased PML-RARa transcripts after induction therapy for acute promyelocytic leukaemia.

ABSTRACT: Objective: To analyze the clinical and biological significance of the acute promyelocytic leukemia (APL) whose PML-RARa transcripts increased after induction therapy.Methods: We analyzed 9 cases of APL whose PML-RARa transcripts increased after induction treatment and compare them with APL whose PML-RARa transcripts decreased.Results: The only factor affecting increased PML-RARa transcripts was the induction protocol. The cases of increased PML-RARa transcripts received induction treatment mainly based on ATRA and ATO. The evaluation of bone marrow aspirate cytology showed that the cell percentage from myelocyte to segmented neutrophil of the patients with increased PML-RARa transcripts was significantly higher than that of the patients with decreased PML-RARa transcripts. In the follow-up, MRD in 9 cases was consistently negative.Conclusions: Our studies showed the increased PML-RARa transcripts after induction treatment had different clinical significance from the decreased PML-RARa transcripts.

SUBMITTER: Liang M

PROVIDER: S-EPMC7877940 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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