Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The main distinctive feature of carcinoma in schistosomal bladder is keratinized squamous cell carcinoma. Keratins/cytokeratins constitute a multigeneic family of structurally related polypeptide markers for the malignant state of epithelial cells. A monoclonal antibody (UNME/K1) regognizing keratins associated with squamous cell carcinoma of the human urinary bladder was generated at the Urology and Nephrology Center, Mansoura, Egypt (UNME), by fusion of spleenocytes from a BALB/c mouse immunized with a keratin extract (K1) of human squamous cell carcinoma and P3X63Ag8/U1 syngeneic myeloma cells. UNME/K1 was purified by a protein-A affinity column and was of the IgG2a type, as determined by immunoelectrophoresis and gel diffusion techniques. When tested against keratins of different types of urinary bladder tumors using enzym linked immunosorbent assay (ELISA), UNME/K1 reacted only with the high molecular weight keratin of squamous cell carcinoma and showed selectivity towards specific histopathological grades of tumors.
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PMID:UNME/K1: an IgG2a monoclonal antibody specific to cytokeratin of human urinary bladder squamous cell carcinoma. 171 97

It has been shown recently that the c-mos oncogene becomes activated in myeloma XRPC-24 via insertion of an intracisternal A particle (IAP) long terminal repeat (LTR). The inserted LTR serves as a promoter from which transcription of the 3' rearranged c-mos initiates. The insertion is in a head-to-head orientation such that the transcriptional orientations of the IAP and the 3' rearranged c-mos are opposite. It has already been shown that this IAP LTR has two promoters, one transcribing the IAP genome and the other transcribing the rearranged c-mos. Since the IAP genomes are actively transcribed in mouse myelomas but not in normal cells, it was interesting to test whether transcriptional activation of the IAP occurs in the presence of active oncogene products, especially nuclear ones. The 5' LTR of the IAP inserted in myeloma XRPC-24 was chosen as a convenient model to test the effect of viral and cellular oncogene products. These included simian virus 40 (SV40) large-T antigen, the adenovirus early 1A (E1A) gene product, the myc gene product, and p53. The LTR was coupled to the bacterial gene coding for chloramphenicol acetyltransferase (CAT) in two orientations, and the levels of CAT directed by the LTR promoters were assayed in either the presence or the absence of the oncogene products. The levels of CAT directed by the 5' LTR promoter transcribing the IAP were significantly elevated in the presence of SV40 large-T antigen, the adenovirus E1A and myc gene products, and p53. The promoter transcribing the rearranged c-mos was transactivated by SV40 large-T antigen and the adenovirus E1A gene product. The results indicate that oncogene products may have an important role in turning on promoters of other genes. The IAP LTR may serve as a useful model for studying the effect of various gene products on promoters which are known to be activated in the malignant state.
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PMID:The long terminal repeat of the intracisternal A particle as a target for transactivation by oncogene products. 293 1

Multiple myeloma (MM) is preceded by the asymptomatic pre-malignant state, monoclonal gammopathy of undetermined significance (MGUS). Although MGUS patients may remain stable for years, they are at increased risk of progressing to MM. A better understanding of the relevant molecular changes underlying the transition from an asymptomatic to symptomatic disease state is urgently needed. Our studies show for the first time that the CD147 molecule (extracellular matrix metalloproteinase inducer) may be having an important biological role in MM. We first demonstrate that CD147 is overexpressed in MM plasma cells (PCs) vs normal and pre-malignant PCs. Next, functional studies revealed that the natural CD147 ligand, cyclophilin B, stimulates MM cell growth. Moreover, when MM patient PCs displaying bimodal CD147 expression were separated into CD147(bright) and CD147(dim) populations and analyzed for proliferation potential, we discovered that CD147(bright) PCs displayed significantly higher levels of cell proliferation than did CD147(dim) PCs. Lastly, CD147-silencing significantly attenuated MM cell proliferation. Taken together, these data suggest that the CD147 molecule has a key role in MM cell proliferation and may serve as an attractive target for reducing the proliferative compartment of this disease.
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PMID:Increased expression of extracellular matrix metalloproteinase inducer (CD147) in multiple myeloma: role in regulation of myeloma cell proliferation. 2246 Jul 57

Recently, the term monoclonal gammopathy of renal significance (MGRS) was introduced to distinguish monoclonal gammopathies that result in the development of kidney disease from those that are benign. By definition, patients with MGRS have B-cell clones that do not meet the definition of multiple myeloma or lymphoma. Nevertheless, these clones produce monoclonal proteins that are capable of injuring the kidney resulting in permanent damage. Except for immunoglobulin light chain amyloidosis with heart involvement in which death can be rapid, treatment of MGRS is often indicated more to preserve kidney function and prevent recurrence after kidney transplantation rather than the prolongation of life. Clinical trials are rare for MGRS-related kidney diseases, except in immunoglobulin light chain amyloidosis. Treatment recommendations are therefore based on the clinical data obtained from treatment of the clonal disorder in its malignant state. The establishment of these treatment recommendations is important until data can be obtained by clinical trials of MGRS-related kidney diseases.
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PMID:How I treat monoclonal gammopathy of renal significance (MGRS). 2410 60

Multiple myeloma is characterized by slowly growing clones of malignant plasma cells in the bone marrow. The malignant state is frequently accompanied by osteolytic bone disease due to a disturbed balance between osteoblasts and osteoclasts. Bone morphogenetic proteins (BMPs) are present in the bone marrow and are important for several aspects of myeloma pathogenesis including growth and survival of tumor cells, bone homeostasis, and anemia. Among cancer cells, myeloma cells are particularly sensitive to growth inhibition and apoptosis induced by BMPs and therefore represent good models to study BMP receptor usage and signaling. Our review highlights and discusses the current knowledge on BMP signaling in myeloma.
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PMID:The role of bone morphogenetic proteins in myeloma cell survival. 2485 40

Recent years have witnessed a dramatic increase in the number of therapeutic options available for the treatment of multiple myeloma (MM) - from immunomodulating agents to proteasome inhibitors to histone deacetylase (HDAC) inhibitors and, most recently, monoclonal antibodies. Used in conjunction with autologous hematopoietic stem cell transplantation, these modalities have nearly doubled the disease's five-year survival rate over the last three decades to about 50%. In spite of these advances, MM still is considered incurable as resistance and relapse are common. While small molecule protein kinase inhibitors have made inroads in the therapy of a number of cancers, to date their application to MM has been less than successful. Focusing on MM, this review examines the roles played by a number of kinases in driving the malignant state and the rationale for target development in the design of a number of kinase inhibitors that have demonstrated anti-myeloma activity in both in vitro and in vivo xenograph models, as well as those that have entered clinical trials. Among the targets and their inhibitors examined are receptor and non-receptor tyrosine kinases, cell cycle control kinases, the PI3K/AKT/mTOR pathway kinases, protein kinase C, mitogen-activated protein kinase, glycogen synthase kinase, casein kinase, integrin-linked kinase, sphingosine kinase, and kinases involved in the unfolded protein response.
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PMID:Kinase inhibitors as potential agents in the treatment of multiple myeloma. 2765 36

B cell activation and differentiation yields plasma cells with high affinity antibodies to a given antigen in a time-frame that allows for host protection. Although the end product is most commonly humoral immunity, the rapid proliferation and somatic mutation of the B cell receptor also results in oncogenic mutations that cause B cell malignancies including plasma cell neoplasms such as multiple myeloma. Myeloma is the second most common hematological malignancy and results in over 100,000 deaths per year worldwide. The genetic alterations that occur in the germinal center, however, are not sufficient to cause myeloma, but rather impart cell proliferation potential on plasma cells, which are normally non-dividing. This pre-malignant state, referred to as monoclonal gammopathy of undetermined significance or MGUS, provides the opportunity for further genetic and epigenetic alterations eventually resulting in a progressive disease that becomes symptomatic. In this review, we will provide a brief history of clonal gammopathies and detail how some of the key discoveries were interwoven with the study of plasma cells. We will also review the genetic and epigenetic alterations discovered over the past 25 years, how these are instrumental to myeloma pathogenesis, and what these events teach us about myeloma and plasma cell biology. These data will be placed in the context of normal B cell development and differentiation and we will discuss how understanding the biology of plasma cells can lead to more effective therapies targeting multiple myeloma.
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PMID:Cell of Origin and Genetic Alterations in the Pathogenesis of Multiple Myeloma. 3123 60