Biomarkers ; metabolism ; Bone Diseases ; metabolism ; Humans ; Multiple Myeloma ; metabolism

Notch signaling pathway is a main pathway through cell-cell interactions, which regulates the programmed cell death, cellular proliferation and differentiation in multiple cell systems, and also is an important signaling pathway to modulate the balance between proliferation and differentiation in hematopoietic environment, and is related with the incidence of multiple hematologic malignancies. Multiple myeloma (MM) is malignant in B cell lineage and characterized by clonal proliferative plasma cells. It is very difficult to cure MM patients with a low proliferation rate of the MM cell and drug resistance to the standard dosage of chemotherapy. In recent years, research has shown that in the malignant plasma cells of the patients with multiple myeloma (MM) and the cell lines, but not in normal plasma cells or tumor cells from patients with other malignancies, the Notch ligand Jagged2 was found to be overexpressed. Jagged2 can induce stromal cells to secrete IL-6, VEGF and IGF-1. Notch activation can interact with NF-kappaB and C-myc to promote the proliferation and to inhibit the apoptosis of MM cells, showing in the relationship between the incidence of myeloma and drug resistance. Inhibition of the Notch signaling pathway may induce the apoptosis of MM cells and enhance the effect of chemotherapy. Study indicated that the specific inhibition of Notch signaling by treatment with a gamma-secretase inhibitor (GSI) alone, a specific pharmacologic inhibitor of Notch signaling, induces the apoptosis of myeloma cells and improves sensitivity of myeloma cell to chemotherapy when combined. In this article the composition of Notch signalling pathway, the mechanism of Notch signalling pathway and the relation of Notch signalling pathway to multiple myeloma were reviewed.
Humans ; Multiple Myeloma ; metabolism ; Receptors, Notch ; metabolism ; Signal Transduction

OBJECTIVE: To study the expression level of serum B-cell maturation antigen (sBCMA) in the peripheral blood of newly diagnosed multiple myeloma (MM) patients, and explore its relationship with the prognosis of MM patients. METHODS: The peripheral blood of 31 newly diagnosed MM patients and 30 healthy volunteers were collected. The level of sBCMA in the peripheral blood was detected by enzyme-linked immunosorbent assay (ELISA). The correlation between the level of sBCMA and the prognosis of MM patients was analyzed. RESULTS: The level of sBCMA in newly diagnosed MM patients was significantly higher than that in healthy controls (P <0.05). The level of sBCMA was closely related to the plasma cells ratio in bone marrow, the M protein level and the treatment (P <0.05). The level of sBCMA was negatively correlated with the overall survival (OS) of MM patients (r =-0.47). MM patients with low expression of sBCMA had significantly longer OS than patients with high expression of sBCMA (P <0.05). CONCLUSION The level of sBCMA is significantly increased in MM patients, which is expected to be a new indicator for evaluating the curative efficacy and prognosis of MM patients. Targeting sBCMA may provide new ideas for the treatment of MM.
Humans ; Multiple Myeloma ; B-Cell Maturation Antigen/metabolism* ; Prognosis

OBJECTIVE: To investigate the expression level and prognostic value of miR-21, miR-18a, miR-146a, and Let-7b derived from serum exosomes in patients with multiple myeloma (MM). METHODS: Serum exosomes were extracted from 57 MM patients and 20 healthy persons using ExoQuick exosome precipitation solution kit, and the relative expression level of miR-21, miR-18a, miR-146a, and Let-7b derived from serum exosomes was measured by RT-qPCR. Correlations of the expression levels of all miRNAs mentioned above with routine laboratory parameters were analyzed by Spearman correlation analysis. The relationship between the expression level of miR-21, miR-18a, miR-146a, and Let-7b derived from serum exosomes and overall survival of patients with MM was analyzed using the Kaplan-Meier survival curve. RESULTS: The expression levels of miR-21, miR-18a, and Let-7b derived from serum exosomes in patients with MM were significantly lower than those in the normal control group (P<0.001), while the expression level of miR-146a between the two groups was not significantly different (P>0.05). The expression level of miR-21 was strongly negatively correlated with serum β₂-microglobulin concentration (r=-0.830), and weakly negatively correlated with serum creatinine, corrected serum calcium, and cystatin C (r=-0.488, -0.282, -0.627). The expression levels of Let-7b and miR-18a were also weakly negatively correlated with the corrected serum calcium, β₂-microglobulin, and cystatin C concentration (r=-0.305, -0.362, -0.461; -0.317, -0.542, -0.434). However, there was no significant correlation between the expression level of miR-146a and routine laboratory parameters in MM patients. The overall survival rate of MM patients with low expression level of miR-21, miR-18a, and Let-7b significantly decreased compared with high expression level group (P<0.05), however, the expression level of miR-146a was not related to the overall survival rate. CONCLUSION Aberrant low expression levels of miR-21, miR-18a, and Let-7b derived from serum exosomes exist in patients with MM, which are associated with a worse overall survival rate.
Calcium/metabolism* ; Creatinine/metabolism* ; Cystatin C/metabolism* ; Exosomes/metabolism* ; Humans ; MicroRNAs/metabolism* ; Multiple Myeloma/metabolism*

Multiple myeloma (MM) is a plasma cell malignancy characterized by the high capacity to induce bone destruction. Osteolytic bone lesions in MM patients mainly result from an increased bone resorption related to the stimulation of osteoclast recruitment and activity. SDF-1a would represent a potential role and may provide a suitable therapeutic target for MM-mediated osteolysis. In this article the structure of SDF-1/CXCR4, the expression of SDF-1/CXCR4 in bone microenvironment of MM patients and its effect on osteoclasts, relation of SDF-1/CXCR expression with osteolytic bone lesions and prognosis of MM, SDF-1/CXCR4 as potential target for treatment of myeloma-osteopathia were reviewed.
Chemokine CXCL12 ; metabolism ; physiology ; Humans ; Multiple Myeloma ; complications ; metabolism ; Osteolysis ; etiology ; Receptors, CXCR4 ; metabolism ; physiology

OBJECTIVETo investigate the role of mesenchymal stem cells (BMSCs) in multiple myeloma (MM) bone marrow (BM) microenrivonment and their effect on myeloma cells survival and bortezomib induced apoptosis.

METHODSBMSCs were derived from BM of untreated myeloma patients (MM-BMSCs) and healthy donors (HD-BMSCs), respectively. The phenotype, proliferation time and cytokine secretion of MM-BMSCs were detected and compared with HD-BMSCs. Then BMSCs were co-cultured with myeloma cell line NCI-H929 and bortezomib in vitro. The NCI-H929 cells proliferation and bortezomib induced cell apoptosis were investigated.

RESULTSMM-BMSCs and HD-BMSCs were isolated successfully. The phenotype of MM-BMSCs was similar to that of HD-BMSCs. Expressions of CD73, CD105, CD44 and CD29 were positive, but those of CD31, CD34, CD45 and HLA-DR (< 1%) negative. The proliferation time of MM-BMSCs was longer than that of HD-BMSCs (82 h vs 62 h, P < 0.05). Moreover, over-expressions of IL-6 and VEGF in MM-BMSCs culture supernatant were detected as compared with that in HD-BMSCs [(188.8 ± 9.4) pg/ml vs (115.0 ± 15.1) pg/ml and (1497.2 ± 39.7) pg/ml vs (1329.0 ± 21.1) pg/ml, respectively]. MM- BMSCs supported survival of the myeloma cells NCI-H929 and protected them from bortezomib induced cell apoptosis.

CONCLUSIONSMM-BMSCs is benefit for myeloma cells proliferation and against cell apoptosis induced by bortezomib. Over-expression of IL-6 and VEGF maybe play a critical role in these effects.

Apoptosis ; drug effects ; Bone Marrow Cells ; cytology ; Bortezomib ; Humans ; Mesenchymal Stromal Cells ; metabolism ; Multiple Myeloma ; metabolism

OBJECTIVETo investigate the effects of CD45 expression on induction of apoptosis in multiple myeloma cells.

METHODSMelphalan was used to induce myeloma cell line U266 apoptosis. Serum-free culture was used to induce CD45RB gene or empty plasmid transfected U266 apoptosis. The glucose-free culture was used to induce high CD45 (CD45(hi)) or low CD45 (CD45(low)) expression AMO1 apoptosis. Intraperitoneal inoculation was used to compare the survival of CD45(-) or CD45(+) U266 cells in mice. The number of apoptotic cells and mitochondrial membrane potential (MMP) was detected by flow cytometry. Western blotting was used to detect the cytochrome C release from mitochondrial and caspase-9 activation.

RESULTSMelphalan treatment induced 45% of CD45(+) and 30% of CD45(-) U266 cells apoptosis. Compared with the CD45(low) AMO1 cells, CD45(hi) cells were more susceptible to apoptosis. In serum-free culture for five days, 60% of CD45RB transferred U266 cells underwent apoptosis, while in the empty plasmid transfected ones, apoptotic cell number was not significantly increased. The survival time of CD45(-) U266 cells in the SCID-hIL-6 mice was 5 times that of CD45(+) cells. After melphalan treatment, 60% of the CD45(+) U266 cells lost MMP, while only 30% of CD45(-) U266 cells, and 10% of control cells did so. After UV irradiation, CD45(+) U266 cells mitochondria released more cytochrome C, leading to more caspase-9 activation.

CONCLUSIONCD45 expression is involved in mitochondria-mediated apoptotic process and increases apoptotic sensitivity of myeloma cells under a variety of stimulation.

Animals ; Apoptosis ; drug effects ; Caspase 3 ; metabolism ; Cell Line, Tumor ; Mice, SCID ; Mitochondria ; Multiple Myeloma ; metabolism

Pten gene is the first antioncogene with dual phosphatase activity discovered so far, pten gene regulates the cell cycle progress, apoptosis, metastasis and invasion of the tumor cells through negatively regulating the multiple signaling transduction pathways. Multiple myeloma (MM) is a malignant tumor occurring in terminal stage of B cell differentiation. The genetic changes are considered as the important factors in MM pathogenesis, among which the deletion of antioncogene is a critical genetic change. However, little is known about the genetic change of pten in MM. This review summarizes the research advance on pten in MM including structure of pten, mechanism of pten effect and correlation of pten with MM in order to provide some references for the investigating new gene target to treat the MM.
Humans ; Multiple Myeloma ; metabolism ; therapy ; PTEN Phosphohydrolase ; genetics ; metabolism ; Signal Transduction

OBJECTIVE: To investigate the significance of detecting serum complement C3 and C4 in patients with multiple myeloma (MM) and to explore its correlation with myeloma bone disease (MBD). METHODS: The levels of serum complement C3 and C4 in 69 MM patients and 30 healthy people were examined by scatter nephelometry. The bone density of L1-4 vertebral body, bilateral femoral neck and bilateral hip joints were measured by dual energy bone density meter (DXA). RESULTS: The levels of serum complement C3 and C4 in MM patients significantly increased in comparison with that in healthy people (P＜0.01). The patients in advanced clinical stage exhibited a higher levels of C3 and C4 than those in stable stage (P＜0.01). In addition, the patients with grade C of MBD had a higher levels of serum complement C3 and C4 than those in patients with grade A and B of MBD (P＜0.01). The levels of serum complement C3 and C4 in MM patients negatively correlated with bone density in L1-4 vertebral body, bilateral femoral necks and hip joints. The correlation coefficients were r=-0.938, r=-0.659, r=-0.745, r=-0.748, r=-0.596 in complement C3 and r=-0.908, r=-0.623, r=-0.710, r=-0.714, r=-0.595 in complement C4, respectively. CONCLUSION The levels of complement C3 and C4 positively correlate with the severity of bone disease and bone density in MM patients, which suggests that complement C3 and C4 plays important roles in the development of MBD. The levels of serum C3 and C4 may be the sensitive biomarkers of MBD.
Biomarkers ; Complement C3 ; metabolism ; Complement C4 ; metabolism ; Femur Neck ; Humans ; Multiple Myeloma

In recent years, studies have found that mitochondrial transfer between leukemic cells and different types of cells in their bone marrow microenvironment, especially mesenchymal stem cells, plays a key role in the occurrence, development and drug resistance of hematological malignant tumors. This paper mainly introduces the role and latest research progress of mitochondrial transfer in acute and chronic myeloid leukemia, acute lymphoblastic leukemia and multiple myeloma, and briefly describes the mechanism of drug resistance caused by mitochondrial transfer in leukemic cells during chemotherapy. The aim is to provide a new idea and theoretical basis for using intercellular mitochondrial transfer as a potential therapeutic target.
Bone Marrow ; Hematologic Neoplasms/metabolism* ; Humans ; Mesenchymal Stem Cells ; Mitochondria ; Multiple Myeloma/metabolism* ; Tumor Microenvironment