Exosomal miR-140-3p produced by bone marrow stromal cells affects acute myeloid leukemia cell growth and apoptosis by targeting SUZ12.

There is growing evidence that exosomes produced by bone marrow stromal cells (BMSCs) are associated with the progression of several cancers, including acute myeloid leukemia (AML), but intrinsic molecular mechanisms remain elusive. Here, we applied previous microarray analysis (GSE133276 and GSE209871) to identify differentially expressed exosomal miRNAs in BMSCs of AML patients, and candidate miR-140-3p, miR-142-5p and miR-142-3p were selected. This study aimed to investigate whether BMSCs affects AML progression are mediated by the candidates, and to explore regulatory mechanisms. The levels of the candidates were examined in bone marrow and BMSCs from AML patients, and exosomes from BMSCs of normal subjects and AML cells by qRT-PCR. Cell proliferation and apoptosis of AML cells co-cultured with BMSCs were detected through CCK-8, colony formation, flow cytometry, and Caspase-3 activity assays with manipulation of the candidate miRNAs expression. RNA pull-down and luciferase reporter assays to identify the downstream target mRNAs of the miRNAs. We confirmed that miR-140-3p, miR-142-5p and miR-142-3p levels were downregulated in bone marrow and BMSCs of AML patients, and were significantly enriched in exosomes of BMSCs but not AML cells. BMSCs co-cultured with AML cells could transfer these miRNAs into AML cells, and suppressed the proliferative potential and promoted the apoptotic behavior of AML cells. Furthermore, miR-140-3p agomir in BMSCs exacerbated the effects of the co-culture system on the AML cell proliferation and apoptosis, which were attenuated by miR-140-3p antagomir. In contrast, co-culture data showed that miR-142-5p and miR-142-3p had no significant effect on cell proliferation and apoptosis. Moreover, SUZ12 polycomb repressive complex 2 subunit (SUZ12) was directly targeted by miR-140-3p, overexpression or inhibition of SUZ12 in AML cells partially counteracted miR-140-3p agomir or antagomir-mediated cellular effects, respectively. Our study suggested that the BMSCs-derived exosomal miR-140-3p, rather than miR-142-5p and miR-142-3p, has a regulatory effect on the growth and apoptosis of AML cells by targeting SUZ12.