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

A high proportion of patients with myelodysplasia show characteristic karyotypic abnormalities in bone marrow cells. The most distinctive of the myelodysplastic syndromes is the 5q- syndrome characterized by refractory anemia, poorly lobulated megakaryocytes, and an interstitial deletion of the long arm of chromosome 5 (5q deletion) as the sole karyotypic abnormality. Recently, several genes encoding hemopoietic growth factors and receptors, comprising the interleukins 3, 4, and 5, macrophage colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor, and the receptor for macrophage-colony-stimulating factor [the CSF1R (formerly FMS) gene product], have been localized to the long arm of chromosome 5, and there has been much speculation that deletion of one or more of these genes may be critical to the pathogenesis of the associated myeloid disorders. One candidate gene is CSF1R, which is required for normal proliferation and differentiation of hemopoietic cells of the myeloid lineage. We have carried out a molecular examination of the CSF1R, both on the 5q- chromosome and on the apparently normal homologous chromosome 5, in 10 patients with myelodysplasia and a 5q deletion. We have found, using restriction fragment length polymorphism analysis and gene dosage experiments, that all 10 patients showed deletion of CSF1R; 6 of 10 were hemizygous and 4 of 10 homozygous for CSF1R loss. The homozygous CSF1R loss has been confirmed in 2 patients by an in situ hybridization technique comparing the signal in affected cells to that in control sex-mismatched cells on the same slides. In those patients considered to have homozygous CSF1R loss by DNA experiments the gene was deleted from the 5q chromosome in all cells and from the apparently normal chromosome 5 in a subset of cells. This loss of one CSF1R allele, together with loss in some cells of the remaining allele on the homologous chromosome 5, in patients with myelodysplasia indicates that this is a region of critical gene loss on 5q. The loss of the hemopoietic growth factor receptor gene CSF1R may be important in the pathogenesis of human myeloid leukemia.
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PMID:Loss of both CSF1R (FMS) alleles in patients with myelodysplasia and a chromosome 5 deletion. 182 36

The GM-CSF receptor belongs to the cytokine receptor superfamily. The high-affinity receptors of this class are lacking intrinsic tyrosine kinase domains. The GM-CSF receptor consists of alpha and beta subunits. The beta subunit is shared with the receptors of IL-3 and IL-5. In addition to the membrane bound forms the receptors have been found to possess soluble isoforms. Since retroviral infection of the human GM-CSF dependent cell line, TF-1, leads to factor independent growth by increased expression of the GM-CSF receptor alpha chain in a subgroup of infected clones, we were interested in studying the role of this chain in human AML. Further considering that a point mutation in the extracellular domain of the erythropoietin receptor, also a member of the cytokine receptor superfamily, resulted in constitutive activation of a murine cell line, we investigated the possibility that a point mutation of the GM-CSF receptor was responsible for autonomous growth of AML cells. We sequenced a segment of the receptor coding for the extracellular domain of the alpha subunit. cDNA was prepared from peripheral blood or bone marrow cells from 24 patients with AML, from four patients with MDS and from three human myeloid cell lines. The region of interest was amplified with two rounds of PCR reactions with nested primers, covering five overlapping fragments, and directly sequenced using a non-radioactive technique. No point mutations were found in the investigated samples. Thus, point mutations in this segment of the GM-CSF receptor gene do not seem to play an important role in the transformation process of human acute leukemia.
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PMID:Absence of point mutations in the extracellular domain of the alpha subunit of the GM-CSF receptor in a series of patients with acute myeloid leukemia (AML). 784 15

A quantitative analysis of expression levels of GM-CSF receptors was performed by flow cytometry in different disease categories, ie AML (n = 72), ALL (n = 18), and MDS (n = 12), as well as 12 healthy volunteers, using three different unconjugated GM-CSF/R monoclonal antibodies (McAbs) (HGM-CSFR (CD116), M5D12, 4B5F5), and appropriate standards. By using the reference HGM-CSFR McAb, in healthy subjects we found detectable levels of GM-CSF/R on blood monocytes (mean MESF (molecules of equivalent soluble fluorochrome)/cell: 36.1 x 10[3]), neutrophils (mean MESF/cell: 7.4 x 10[3]), bone marrow (BM) myelo-monocytic precursors (MESF range for the myeloid component, ie promyelocytes, myelocytes, metamyelocytes: 11.7-40.5 x 10[3], and for the monocytic lineage: 25.7-69.2 x 10[3]), and in two distinct subsets of BM CD34+ progenitor cells (GM-CSF/R dim: 2.5 x 10[3] MESF/cell, GM-CSF/R bright (10% of the total number of CD34 cells: 22.0 x 10[3] MESF/cell). In these subjects, there was no correlation between the expression levels of GM-CSF/R and CFU (CFU-GM, CFU-GEMM, BFU-E) colony production. Among the AML samples, M5D12 McAb was positive in 33%, 4B5F5 McAb in 90%, and HGM-CSF/R McAb in 78% of the cases examined (range of MESF/cell for the HGM-CSFR McAb: 0.9 x 10[3]-106.7 x 10[3]). The highest MESF values were seen in the M5 FAB subvariety (mean: 39.4 x 10[3]), where all the patients tested (n = 20) showed a strong positivity for the HGM-CSFR McAb. On the contrary, all ALL samples were GM-CSF/R negative except in two patients, who displayed a dim GM-CSF/R positivity (My+ALL: 1.3 x 10[3] MESF/cell; pro-B ALL: 1.0 x 10[3] MESF/cell). In most (>70%) M1 FAB subtypes, GM-CSF/R+ blasts co-expressed CD34low, HLA-DRhigh, CD33, CD38 antigens, and had little or no capacity to form CFU-GM colonies. GM-CSF/R+ blasts from the M5 FAB category were also positive for CD14, CD11c, CD33 and CD87. Furthermore, the number of GM-CSF/R expressed by leukemic cells from five out of 72 (7%) AML patients was above the highest values seen in normal samples (>69.2 x 10[3] MESF/cell), allowing the possibility of using this marker for the monitoring of the minimal residual disease (MRD) in a subset of AML. Cell culture studies aimed at evaluating GM-CSF receptor modulation following AML blast exposure to rhGM-CSF showed two distinct patterns of response; in the first group (6/10 cases) rhGM-CSF down-modulated GM-CSF receptors, whereas in the second group (4/10 cases), rhGM-CSF treatment was associated with either an increase or no change in the number of GM-CSF/R. In conclusion, cellular GM-CSF/R expression was variable and ranged from undetectable (ALL and a minority of AML) to very high intensities in M5 AML, and were also documented in some M0 AML, thus suggesting the concept that GM-CSF/R detection may be of help in lineage assignment of undifferentiated forms. Since the number of GM-CSF/R on AML blasts may be modulated after GM-CSF treatment, it can be postulated that the clinical use of GM-CSF in this disease may be optimized by a dynamic analysis of the number and the affinity status of GM-CSF-R in blasts and normal hemopoietic cells.
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PMID:Flow cytometry measurement of GM-CSF receptors in acute leukemic blasts, and normal hemopoietic cells. 932 92

The proliferative and differentiative response of neutrophils to granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to be impaired in patients with myelodysplastic syndromes (MDS). To investigate the mechanisms of the defective response in MDS, we examined expression levels of GM-CSF receptor alpha (GMR alpha) and common beta (beta c) subunits on CD16(+) neutrophils, CD14(+) monocytes and CD3(+) T cells from 26 MDS patients and 10 healthy controls using flow cytometry. Expression of GMR alpha was significantly decreased on the neutrophils of five out of 26 patients and was not specific for any FAB subtype. In contrast, beta c expression on neutrophils was significantly reduced in 14 out of 26 patients with a higher proportion occurring in the advanced stages of MDS including refractory anaemia with excess of blasts (RAEB), RAEB in transformation (RAEBt) and overt leukaemia compared with refractory anaemia (RA)/RA with ringed sideroblasts (RARS) or healthy controls. Decreased beta c also correlated with the degree of hypogranular neutrophil morphology and increased infection. Expression of both subunits on T cells and monocytes in MDS was similar to normal controls. Polymerase chain reaction amplification of reverse-transcribed mRNA isolated from the affected neutrophils suggests that the reduction of beta c may result from decreased message levels. The observed reduction in GM-CSF receptor expression could account for the impaired proliferative and maturational responses in MDS.
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PMID:Neutrophil-specific reduction in the expression of granulocyte--macrophage colony-stimulating factor receptor subunits in myelodysplastic syndromes. 1112 48

Continuous human leukemia-lymphoma (LL) cell lines represent a rich resource of abundant, accessible and manipulable living cells contributing significantly to a better understanding of the pathophysiology of hematopoietic tumors. In particular, classical and molecular cytogenetics have benefitted enormously from the availability of LL cell lines with specific chromosomal abnormalities. Such aberrations may be the portal to the discovery of novel oncogene rearrangements for which positive cell lines provide a resource for both discovery and functional studies. The new continuous leukemia cell line MUTZ-11 was established in 1994 from the peripheral blood of a 60-year-old woman with acute myeloid leukemia (AML) M4 (following 2 years with myelodysplastic syndromes). DNA fingerprinting confirmed the authenticity and derivation of the cell line. The immunoprofile as determined by flow cytometry was as follows: positive for myelocytic markers (CD13, CD15, CD33, CD65 and CD68), negative for T-cell (except for CD4 and CD7), B-cell and erythroid-megakaryocytic markers. The cell line is constitutively cytokine-dependent and growth depends on externally added cytokines. With regard to cytokine receptor expression, the cell line was found to be positive for GM-CSFRalpha (granulocyte-macrophage colony-stimulating factor receptor, CD116), Kit (CD117) and IL-3Ralpha (interleukin-3 receptor, CD123). The cytokine response profiles as determined by [(3)H]-thymidine incorporation assay were: 2-to-12 fold growth stimulation of MUTZ-11 by GM-CSF, IFN-alpha (interferon), IFN-beta, IFN-gamma, IL-3 and SCF (stem cell factor); growth inhibition by TGF-beta1 (transforming growth factor), TNF-alpha (tumor necrosis factor) and TNF-beta. Cytogenetic analysis showed the following consensus karyotype: 46, XX, der(16)t(16;17)(p13.3;q23)x2. Previous molecular biological analysis documented that MUTZ-11 cells carry both an FLT3 internal tandem duplication (ITD) and an MLL partial tandem duplication (PTD). The scientific significance of MUTZ-11 lies (i). in the absolute cytokine-dependency and the proliferative response to various cytokines, (ii). in the unique cytogenetic (disomic t(16;17)) and (iii). molecular biological alterations (FLT3 ITD + MLL PTD). In summary, the new cytokine-dependent AML-derived cell line MUTZ-11 displays unique novel features and emphasizes the need for comprehensive analysis of new LL cell lines which may lead to the discovery of important pathogenetic alterations.
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PMID:New cytokine-dependent acute myeloid leukemia cell line MUTZ-11 with disomic chromosome rearrangement t(16;17). 1506 4

The aim of this article was to explore the pathogenetic differences, as well as to provide a new way for the differential diagnosis of these two diseases by comparative analysis of CD(34)(+) cells numbers and their surface expression of granulocyte colony-stimulating factor receptor (G-CSFR) and granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) in patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS). Twenty-seven patients with AA, 45 patients with MDS, and 20 normal controls were enrolled in this study. The ratio of CD(34)(+) cells and their surface expression of G-CSFR and GM-CSFR were detected by flow cytometry (FCM). The ratio of CD(34)(+) cells in BMMNC of AA, MDS patients and controls were 0.2438 +/- 0.1129%, 2.1677 +/- 1.1345% and 1.0792 +/- 0.3221%, respectively. Compared with normal controls as well as MDS patients, the ratio of CD(34)(+) cells in BMMNC of AA was significantly reduced (P < 0.05). The ratio of CD(34)(+) cells in MDS was significantly elevated than controls (P < 0.05). The ratio of CD(34)(+) cells in BMMNC of MDS-RA and MDS-RAEB patients were 1.2821 +/- 0.4658% and 3.7729 +/- 2.3360%, respectively. Compared with normal controls and MDS-RA patients, the ratio of CD(34)(+) cells in MDS-RAEB was significantly elevated (P < 0.05). The ratio of CD(34)(+) cells in MDS-RA was significantly elevated than AA patients (P < 0.05). The surface expression of G-CSFR on CD(34)(+) cells of AA, MDS patients and controls were 34.402 +/- 21.8357%, 26.376 +/- 15.2895% and 21.443 +/- 7.4465%, respectively. The surface expression of G-CSFR on CD(34)(+) cells of MDS-RA and MDS-RAEB patients were 22.788 +/- 14.7628% and 30.682 +/- 15.5346%. The surface expression of GM-CSFR on CD(34)(+) cells of AA, MDS patients and controls were 6.5961 +/- 4.4322%, 18.2737 +/- 10.9841% and 4.2753 +/- 2.6249%, respectively. Compared with AA and controls, the expression of GM-CSFR in MDS patients was significantly elevated (P < 0.05). The surface expression of GM-CSFR on CD(34)(+) cells of MDS-RA and MDS-RAEB patients were 16.1625 +/- 6.9487% and 22.1003 +/- 14.2983%. In AA patients, the ratio of CD(34)(+) cells in BMMNC less than 0.1% accounts for 75% (6/8) SAA patients, compared with 10.55% (2/19) in CAA (P < 0.05). The detection of CD(34)(+) cells and their surface expression of granulocyte (macrophage) colony-stimulating factor receptors G (M)-CSFR in AA and MDS are helpful in the differential diagnosis or prognosis of these two disorders.
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PMID:Comparative analysis of G-CSFR and GM-CSFR expressions on CD34+ cells in patients with aplastic anemia and myelodysplastic syndrome. 1863 7

We identified 18 patients with the distinct clinical phenotype of susceptibility to disseminated nontuberculous mycobacterial infections, viral infections, especially with human papillomaviruses, and fungal infections, primarily histoplasmosis, and molds. This syndrome typically had its onset in adulthood (age range, 7-60 years; mean, 31.1 years; median, 32 years) and was characterized by profound circulating monocytopenia (mean, 13.3 cells/microL; median, 14.5 cells/microL), B lymphocytopenia (mean, 9.4 cells/microL; median, 4 cells/microL), and NK lymphocytopenia (mean, 16 cells/microL; median, 5.5 cells/microL). T lymphocytes were variably affected. Despite these peripheral cytopenias, all patients had macrophages and plasma cells at sites of inflammation and normal immunoglobulin levels. Ten of these patients developed 1 or more of the following malignancies: 9 myelodysplasia/leukemia, 1 vulvar carcinoma and metastatic melanoma, 1 cervical carcinoma, 1 Bowen disease of the vulva, and 1 multiple Epstein-Barr virus(+) leiomyosarcoma. Five patients developed pulmonary alveolar proteinosis without mutations in the granulocyte-macrophage colony-stimulating factor receptor or anti-granulocyte-macrophage colony-stimulating factor autoantibodies. Among these 18 patients, 5 families had 2 generations affected, suggesting autosomal dominant transmission as well as sporadic cases. This novel clinical syndrome links susceptibility to mycobacterial, viral, and fungal infections with malignancy and can be transmitted in an autosomal dominant pattern.
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PMID:Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia. 2004 Jul 66