MicroRNA‐34a‐mediated death of acute myeloid leukemia stem cells through apoptosis induction and exosome shedding inhibition via histone deacetylase 2 targeting

Abstract

We investigated the role of leukemia stem cells in chemoresistance and recurrence of acute myeloid leukemia. Total RNA was isolated from cells or tissues using TRIzol reagent. Cell viability was assessed with the tetrazolium assay. MicroRNA‐34a (miR‐34a), which acts on cell death regulation pathways, was noticeably downregulated in non‐M3 acute myeloid leukemia stem cells compared with normal hematopoietic stem cells. Furthermore, inhibition of miR‐34a‐mediated suppression in leukemia stem cells was associated with poor clinical outcomes and impaired treatment efficacy in acute myeloid leukemia. Transfection with a miR‐34a mimic triggered leukemia stem cell death and prevented leukemia. Bioinformatics analysis and a dual‐luciferase reporter assay showed that miR‐34a targeted the 3′‐untranslated region of histone deacetylase 2, and the reinforced expression of miR‐34a remarkably stimulated the expression of histone deacetylase 2 in leukemia stem cells. Ectopic miR‐34a expression triggered death of leukemia stem cells via pathways involving the Janus kinase 1‐signal transducer and activator of transcription 2‐p53 axis. Targeting leukemia stem cells to trigger cell death through upregulation of miR‐34a expression could be used to diagnose and treat acute myeloid leukemia.

The Landscape of Exosome-Derived Non-Coding RNA in Leukemia

“…Therefore, finding strategies to specifically eliminate LSCs may be necessary for solving AML recurrence or drug resistance ( Peng et al, 2018 ). Hu et al (2020) found that miR-34a was elevated in exosomes derived from LSCs. miR-34a could impede the secretion of exosomes which was promoted by RAB27B through inhibiting the expression of RAB27B.…”

“…This process could increase the miR-34a level of LSCs in which miR-34a could inhibit HDAC2 expression and regulated the JAK1/STAT2/p53 pathway to promote the clearance of LSCs. However, LSCs took away the tumor-suppressive miR-34a by secreting exosomes, leading to the decrease of miR-34a in LSCs and the abnormal proliferation of LSCs ( Hu et al, 2020 ). Similarly, miR-34c-5p has also been observed to promote LSCs clearance whereas RAB27B-mediated extracellular transfer of miR-34c-5p through exosomes partly promoted the miR-34c-5p decrease in LSCs, thus promoting the growth of LSCs ( Peng et al, 2018 ).…”

The role of exosomes in cancer‐related programmed cell death

“…In non‐M3 acute myeloid leukemia stem cells, MicroRNA‐34a (miR‐34a) is significantly downregulated compared with normal hematopoietic stem cells. However, miR‐34a induces apoptosis by targeting histone deacetylase 2, and the inhibition of exosome shedding mediates stem cell death in acute myeloid leukemia 57 . Exosomes produced by cancer cells are known to regulate lung cancer development by promoting epithelial‐mesenchymal transition of tumor cells, inducing angiogenesis, establishing a premetastatic microenvironment, and evading the immune system 58 .…”

Exosome: From leukemia progression to a novel therapeutic approach in leukemia treatment

“…Apparently, miR‐181a or a specific EV has a role in central nervous system involvement in Pediatric Acute Lymphoblastic Leukemia (PALL) and miR‐181a inhibitor may show hopeful results in PALL treatment 137 . miR‐34a is highly efficient in the treatment of AML patients via inhibiting exosome releasing and inducing cell death by increasing the expression of the Janus Kinase 1/Signal Transducer and Activator of Transcription protein‐2 (JAK1/STAT2)/p53 pathway 138 . Regarding the role of exosomal miR‐222‐3p derived from BM‐MSCs in inducing apoptosis by interferon regulatory factor 2 signaling pathway and inhibiting cell proliferation, they can be a novel therapeutic approach in myeloid leukemia 139 .…”

“…137 miR-34a is highly efficient in the treatment of AML patients via inhibiting exosome releasing and inducing cell death by increasing the expression of the Janus Kinase 1/Signal Transducer and Activator of Transcription protein-2 (JAK1/STAT2)/p53 pathway. 138 Regarding the role of exosomal miR-222-3p derived from BM-MSCs in inducing apoptosis by interferon regulatory factor 2 signaling pathway and inhibiting cell proliferation, they can be a novel therapeutic approach in myeloid leukemia. 139 Interestingly, a prior study focusing on serum exosomal miRNA-125b in AML patients identified an up-regulation of this miRNA to be strongly associated with elevation of relapse and risk of mortality.…”