Extracellular vesicles derived from T-cell acute lymphoblastic leukemia inhibit osteogenic differentiation of bone marrow mesenchymal stem cells <i>via</i> miR-34a-5p

Abstract

Reduced bone formation in patients with T-cell acute lymphoblastic leukemia (T-ALL) may be related to the interaction between tumour cells and bone marrow stromal cells (BMSCs). The miRNAs in extracellular vesicles derived from leukemia cells play an essential role in regulating the function of BMSCs; however, the regulatory mechanisms remain unclear. The expression of miR-34a-5p in T-ALL patients and cells was measured by quantitative real-time PCR. BMSCs were co-cultured with extracellular vesicles isolated from T-ALL cells in mineralization medium. The osteogenic differentiation of BMSCs was evaluated by Alizarin Red S staining, alkaline phosphatase (ALP) staining, and detection of osteogenic differentiation markers. A dual-luciferase reporter assay was performed to confirm the targeting relationship between miR-34a-5p and Wnt family member 1 (WNT1). MiR-34a-5p expression was upregulated in T-ALL patients and Jurkat cells. After BMSCs were co-cultured with extracellular vesicles derived from T-ALL cells, osteogenic differentiation of BMSCs was inhibited, and bone mineralization and ALP activity were decreased compared to those of control cells. MiR-34a-5p knockdown in T-ALL cells restored osteogenic differentiation of BMSCs co-cultured with extracellular vesicles. In addition, miR-34a-5p targets and negatively regulates WNT1 expression. In conclusion, our results demonstrated that knockdown of miR-34a-5p in extracellular vesicles derived from T-ALL cells promoted osteogenic differentiation of BMSCs by regulating WNT1.

BM-MSCs display altered gene expression profiles in B-cell acute lymphoblastic leukemia niches and exert pro-proliferative effects via overexpression of IFI6

“…In our current work, MSCs in the leukemia niche had attenuated osteogenic and adipogenic differentiation abilities, and displayed varying degrees of senescence changes, showing agreement with prior studies by Bonilla et al [ 13 ], Yang et al [ 27 ] and Vanegas et al [ 14 ]. Yuan et al [ 28 ] also showed that after co-culture of MSCs with T-ALL cell-derived extracellular vesicles, the MSCs exhibited suppressed differentiation towards osteogenesis. In terms of apoptosis and cell cycle, we just observed changes in the MSC–Nalm-6 co-culture system.…”

Cell Type-Specific Extracellular Vesicles and Their Impact on Health and Disease

“…For detecting castrate-resistant prostate cancer, a form of prostate cancer that persists after androgen depletion therapy, the presence of androgen receptor AR-Variant 7 in plasma-derived EVs was of special interest [ 110 ]. In one of the more common forms of leukemia, acute lymphoblastic leukemia (ALL), leukemic cells released EVs containing miR-43a-5p to the bone marrow [ 111 ]—which caused the inhibition of osteogenesis, leading to leukemia progression [ 112 ]. In acute myeloid leukemia (AML), a panel of miRNAs from serum EVs can be used to distinguish leukemic mice from controls [ 110 , 113 ].…”

Extracellular vesicles in hematological malignancies: EV-dence for reshaping the tumoral microenvironment

“…The osteogenic differentiation of BM-MSCs is inhibited by miR-34a-5p carried by sEVs released by T-ALL blasts. Yuan and colleagues described overexpression of miR-34a-5p in T-ALL patient cells, in cell lines and in their corresponding sEVs ( 99 ). Furthermore, miR-34a-5p overexpression coincides with reductions in WNT and β-catenin expression and, consequently, osteogenic differentiation ( 99 ).…”

“…Yuan and colleagues described overexpression of miR-34a-5p in T-ALL patient cells, in cell lines and in their corresponding sEVs ( 99 ). Furthermore, miR-34a-5p overexpression coincides with reductions in WNT and β-catenin expression and, consequently, osteogenic differentiation ( 99 ). Hematopoietic stem cell populations are gravely affected by ALL shed EVs, altered cytokine secretion, exhaustion, and failure to maintain HSC niche can be caused by these vesicles ( 94 , 97 , 100 ).…”