Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The FMS gene encodes the functional cell surface receptor for colony-stimulating factor 1, the macrophage- and monocyte-specific growth factor. Codons 969 and 301 have been identified as potentially involved in promoting the transforming activity of FMS. Mutations at codon 301 are believed to lead to neoplastic transformation by ligand independence and constitutive tyrosine kinase activity of the receptor. The tyrosine residue at codon 969 has been shown to be involved in a negative regulatory activity, which is disrupted by amino acid substitutions. This study reports on the frequency of point mutations at these codons, in vivo, in human myeloid malignancies and in normal subjects. We studied 110 patients [67 with myelodysplasia (MDS) and 48 with acute myeloblastic leukemia (AML)], 5 patients being studied at the MDS and the later AML stage of the disease. There was a total incidence of 12.7% (14/110) with mutations in codon 969 and 1.8% (2/110) with mutations in codon 301. Two patients had mutations in the AML stage of the disease but not in the preceding MDS and one had a mutation in the MDS stage but not upon transformation of AML. This is consistent with the somatic origin of these mutations. FMS mutations were most prevalent (20%) in chronic myelomonocytic leukemia and AML type M4 (23%), both of which are characterized by monocytic differentiation. One of 51 normal subjects had a constitutional codon 969 mutation, which may represent a marker for predisposition to myeloid malignancy.
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PMID:FMS mutations in myelodysplastic, leukemic, and normal subjects. 240 20

The PRV-1 gene has been proposed as a marker of polycythaemia vera (PV). PRV-1 and NB1 are alleles of the polymorphic gene CD177, which belongs to the Ly-6/uPAR superfamily, and their coding regions differ at only four nucleotides. We studied neutrophil CD177 mRNA levels in normal subjects and in 235 patients with Ph-negative chronic myeloproliferative disorders (CMD), including PV, essential thrombocythaemia and myelofibrosis with myeloid metaplasia. Additional disease states were investigated for comparison. Highly variable neutrophil CD177 mRNA levels were observed in normal individuals. Neutrophils isolated from the bone marrow, or from peripheral blood following granulocyte colony-stimulating factor administration showed markedly higher CD177 expression than circulating granulocytes on steady state. Increased neutrophil CD177 mRNA levels were detected in all CMD. Elevated values were also found in reactive conditions and in disorders such as chronic myeloid leukaemia and myelodysplastic syndromes. In the differential diagnosis between PV and secondary erythrocytosis, the assay sensitivity was 68% while its specificity was 60%. These findings indicate that an elevated neutrophil CD177 mRNA level is not a specific marker for the diagnosis of PV nor for that of CMD. From a clinical viewpoint, neutrophil CD177 mRNA overexpression is rather a marker of abnormal neutrophil production and/or release in patients with CMD.
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PMID:Clinical significance of neutrophil CD177 mRNA expression in Ph-negative chronic myeloproliferative disorders. 1532 15

The bone marrow is the major site of haemopoiesis in adult human. It contains cells that represent the stages in the development of different types of blood cells e.g. myelocytes, metamyelocytes, erythroblasts, reticulocytes, and other lymphoid progenies etc. Bone marrow failure is primarily the result of a specific failure of bone marrow precursor cells to produce mature cells. N-ethyl N-nitroso urea (ENU) is one of the most potent mutagens that can create an abnormal bone marrow microenvironment by causing defect in haematopoietic stem cell maturation cascade. ENU is easy to administer in mouse, and some probable mutations can be helpful to create models of human diseased conditions like Myelodysplastic syndrome (MDS). MDS is considered as an intravascular bone marrow disorder, a combined structural-functional abnormality wherein the differentiation procedure of the bone marrow stem cell is either incomplete or defective. We assumed that Myelodysplastic syndrome stands in between an inhibitory cellular pattern and a positive overshoot of abnormal differentiations representing an unknown juncture where the mystery of aplasia and leukemia hide back. Instead of using a transgenic mouse model, we attempted to develop an experimentally induced murine model of preleukemia or human MDS like disease model. In doing so ENU has been administered i.p and the animals were examined on thirtieth day and peripheral blood haemogram was documented. Upon registering the appearance of abnormal peripheral blood scenario, the changes in the intravascular bone marrow (BM) architecture, cell surface receptor expression, e.g. Sca-1, c-Kit and the early and late phase apoptic patterns were noted. The results represented an interesting correlation in between bone marrow architecture, early stem cell receptor and apoptic marker expression resembling human MDS.
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PMID:Sca-1 / c-Kit receptor expression and apoptosis pattern in ENU induced MDS mice. 2072 May 96

The formation of erythroid progenitor cells depends sharply upon erythropoietin (EPO), its cell surface receptor (erythropoietin receptor, EPOR), and Janus kinase 2 (JAK2). Clinically, recombinant human EPO (rhEPO) additionally is an important anti-anemia agent for chronic kidney disease (CKD), myelodysplastic syndrome (MDS) and chemotherapy, but induces hypertension, and can exert certain pro-tumorigenic effects. Cellular signals transduced by EPOR/JAK2 complexes, and the nature of EPO-modulated signal transduction factors, therefore are of significant interest. By employing phospho-tyrosine post-translational modification (p-Y PTM) proteomics and human EPO- dependent UT7epo cells, we have identified 22 novel kinases and phosphatases as novel EPO targets, together with their specific sites of p-Y modification. New kinases modified due to EPO include membrane palmitoylated protein 1 (MPP1) and guanylate kinase 1 (GUK1) guanylate kinases, together with the cytoskeleton remodeling kinases, pseudopodium enriched atypical kinase 1 (PEAK1) and AP2 associated kinase 1 (AAK1). Novel EPO- modified phosphatases include protein tyrosine phosphatase receptor type A (PTPRA), phosphohistidine phosphatase 1 (PHPT1), tensin 2 (TENC1), ubiquitin associated and SH3 domain containing B (UBASH3B) and protein tyrosine phosphatase non-receptor type 18 (PTPN18). Based on PTPN18's high expression in hematopoietic progenitors, its novel connection to JAK kinase signaling, and a unique EPO- regulated PTPN18-pY389 motif which is modulated by JAK2 inhibitors, PTPN18's actions in UT7epo cells were investigated. Upon ectopic expression, wt-PTPN18 promoted EPO dose-dependent cell proliferation, and survival. Mechanistically, PTPN18 sustained the EPO- induced activation of not only mitogen-activated protein kinases 1 and 3 (ERK1/2), AKT serine/threonine kinase 1-3 (AKT), and signal transducer and activator of transcription 5A and 5B (STAT5), but also JAK2. Each effect further proved to depend upon PTPN18's EPO- modulated (p)Y389 site. In analyses of the EPOR and the associated adaptor protein RHEX (regulator of hemoglobinization and erythroid cell expansion), wt-PTPN18 increased high molecular weight EPOR forms, while sharply inhibiting the EPO-induced phosphorylation of RHEX-pY141. Each effect likewise depended upon PTPN18-Y389. PTPN18 thus promotes signals for EPO-dependent hematopoietic cell growth, and may represent a new druggable target for myeloproliferative neoplasms.
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PMID:Phospho-PTM proteomic discovery of novel EPO- modulated kinases and phosphatases, including PTPN18 as a positive regulator of EPOR/JAK2 Signaling. 3202 48