ABSTRACT
The intercellular communication between leukemia cells and bone marrow mesenchymal stem cells (BM-MSCs) plays more important role in chronic myeloid leukemia (CML) than we previously understood. Recently, we found that microvesicles released from human leukemia cell line K562 (K562-MVs) containing BCR-ABL1 mRNA malignantly transformed normal hematopoietic transplants. Here, we investigated whether K562-MVs contribute to the transformation of human bone marrow mesenchymal stem cells (BM-MSCs). We showed that K562-MVs could be integrated into co-cultured normal BM-MSCs and dose-dependently enhanced the proliferation of BM-MSCs. Meanwhile, K562-MVs (400 ng/mL) significantly increased the expression of BCR-ABL1 in these BM-MSCs, accompanied by the enhanced secretion of TGF-ß1. These BM-MSCs in turn could trigger the TGF-ß1-dependent proliferation of K562 cells. Moreover, we confirmed the presence of BCR-ABL1 in circulating MVs from 11 CML patients. Compared to the normal BM-MSCs, the BM-MSCs from CML patients more effectively increased the BCR-ABL1 expression and TGF-ß1 secretion in K562 cells as well as the proliferation of K562 cells. Our findings enrich the mechanisms involved in the interaction between leukemia cells and BM-MSCs and provide novel ways to monitor minimal residual disease and worthwhile approaches to treat CML.
Subject(s)
Bone Marrow Cells/metabolism , Cell Communication , Cell Transformation, Neoplastic/genetics , Cell-Derived Microparticles/genetics , Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Mesenchymal Stem Cells/metabolism , Adolescent , Adult , Bone Marrow Cells/pathology , Cell Proliferation , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Cell-Derived Microparticles/pathology , Cell-Free Nucleic Acids/blood , Cell-Free Nucleic Acids/genetics , Coculture Techniques , Female , Fusion Proteins, bcr-abl/blood , Humans , K562 Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/blood , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Male , Mesenchymal Stem Cells/pathology , Middle Aged , RNA, Messenger/blood , RNA, Messenger/genetics , Time Factors , Transforming Growth Factor beta1/metabolism , Tumor Microenvironment , Young AdultABSTRACT
Coronary artery disease (CAD) causes more than 700,000 deaths each year in China. Previous genome-wide association studies (GWAS) in populations of European ancestry identified several genetic loci for CAD, but no such study has yet been reported in the Chinese population. Here we report a three-stage GWAS in the Chinese Han population. We identified a new association between rs6903956 in a putative gene denoted as C6orf105 on chromosome 6p24.1 and CAD (P = 5.00 × 10⻳, stage 2 validation; P = 3.00 × 10⻳, P = 1.19 × 10â»8 and P = 4.00 × 10⻳ in three independent stage 3 replication populations; P = 4.87 × 10⻹², odds ratio = 1.51 in the combined population). The minor risk allele A of rs6903956 is associated with decreased C6orf105 mRNA expression. We report the first GWAS for CAD in the Chinese Han population and identify a SNP, rs6903956, in C6orf105 associated with susceptibility to CAD in this population.
