AML-derived mesenchymal stem cells upregulate CTGF expression through the BMP pathway and induce K562-ADM fusiform transformation and chemoresistance

Abstract

Bone marrow-derived mesenchymal stem cells (MSCs), are the basic cellular components that make up the bone marrow microenvironment (BMM). In acute myeloid leukemia (AML), the morphology and function of MSCs changes in accordance with the transformation of the BMM. Moreover, the transformation of MSCs into osteoblasts is determined through the bone morphogenetic protein (BMP) pathway, ultimately leading to an altered expression of the downstream adhesion molecule, connective tissue growth factor (CTGF). In this study, we aimed to explore the interaction of possible pathways in AML-derived mesenchymal stem cells (AML-MSCs) co-cultured with the K562 and K562-ADM cell lines. AML-MSCs were co-cultured with K562/K562-ADM cells, and the interactions between the cells were verified by morphological detection, peroxidase staining (POX), reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and fluorescence in situ hybridization (FISH). The proliferation of K562/K562-ADM cells under co-culture conditions was detected by flow cytometry. The expression levels of BMP4 and CTGF were examined by RT-qPCR and western blot (WB) analysis. The detection of interleukin (IL)-6 and IL-32 was also determined by enzyme linked immunosorbent assay (ELISA). In the co-culture system, the K562-ADM cells underwent fusiform transformation. The occurrence of this transformation was associated with an increased expression of CTGF due to the dysregulation of the BMP pathway. The AML-MSCs promoted the proliferation of the K562-ADM cell, but inhibited that of the K562 cells. These findings were confirmed by changes in the expression of the soluble cytokines, IL-6 and IL-32. On the whole, the findings of this study demonstrate that AML-MSCs regulate the expression of CTGF through the BMP pathway. In addition, they affect cytokine production, induce spindle-shaped transformation, and increase drug resistance in the K562-ADM cells. Thus, the morphological transformation through the BMP pathway provides us with a novel target with which to circumvent tumor occurrence, development, drug resistance, invasion and metastasis.