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)

The membrane-proximal cytoplasmic region of the granulocyte colony-stimulating factor receptor (G-CSFR) is known to be essential for the proliferation signal, with a more distal region being required for the differentiation signal. Such a separation of functional domains raises the possibility that mutations occurring at these regions may contribute to cell proliferation in the absence of differentiation, this being the most important characteristic in acute leukemia cells. Therefore, we analysed the structural abnormalities at the transmembrane and cytoplasmic region of G-CSFR in a significant number of patients with various myeloid malignancies. When we examined the genomic DNA of G-CSFR obtained from 41 patients with acute myelogenous leukemia (AML), 18 with chronic myelogenous leukemia (CML), 7 with myelodysplastic syndrome (MDS), 2 with chronic myelomonocytic leukemia and 1 with chronic neutrophilic leukemia, we found a polymorphism in 3 patients, but no significant pathogenic mutations in any patients. The screening for this polymorphism in 100 hematologically normal controls revealed that it may be useful as a linkage marker for population and family studies, because the heterozygosity index is at a high level (0.055). While there have been several reports discussing the leukemogenic potential of mutations in the cytokine/hematopoietin receptor superfamily, genetic alterations in the transmembrane and cytoplasmic region of G-CSFR do not seem to play a pathogenic role in leukemia.
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PMID:Analysis of the granulocyte colony-stimulating factor receptor gene structure using PCR-SSCP in myeloid leukemia and myelodysplastic syndrome. 954 19

In approximately 20% of cases of severe congenital neutropenia (SCN), mutations are found in the gene encoding the granulocyte colony-stimulating factor receptor (G-CSF-R). These mutations introduce premature stop codons, which result in truncation of 82-98 COOH-terminal amino acids of the receptor. SCN patients who develop secondary myelodysplastic syndrome and acute myeloid leukemia almost invariably acquired a GCSFR mutation, suggesting that this genetic alteration represents a key step in leukemogenesis. Here we show that an equivalent mutation targeted in mice (gcsfr-Delta715) results in the selective expansion of the G-CSF- responsive progenitor (G-CFC) compartment in the bone marrow. In addition, in vivo treatment of gcsfr-Delta715 mice with G-CSF results in increased production of neutrophils leading to a sustained neutrophilia. This hyperproliferative response to G-CSF is accompanied by prolonged activation of signal transducer and activator of transcription (STAT) complexes and extended cell surface expression of mutant receptors due to defective internalization. In view of the continuous G-CSF treatment of SCN patients, these data provide insight into why progenitor cells expressing truncated receptors clonally expand in vivo, and why these cells may be targets for additional genetic events leading to leukemia.
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PMID:Sustained receptor activation and hyperproliferation in response to granulocyte colony-stimulating factor (G-CSF) in mice with a severe congenital neutropenia/acute myeloid leukemia-derived mutation in the G-CSF receptor gene. 998 83

Myelodysplastic syndromes (MDS) are clonal disorders in which the proper differentiation of hematopoietic stem cells is impaired. There is no effective treatment for this stem cell disorder at present. In an attempt to find a new strategy that promotes the differentiation of MDS blast cells, we tried retroviral transduction of granulocyte colony-stimulating factor receptor (G-CSFR) into an interleukin-3-dependent MDS cell line, MDS-L, since expression of G-CSFR is known to be essential for the differentiation of myeloid progenitor cells and this expression is impaired in most MDS cells. Ectopic expression of human G-CSFR cDNA in MDS-L cells gave rise to granulocytic differentiation by G-CSF stimulation. G-CSF caused the transformants expressing G-CSFR to display a morphological characteristic of mature granulocytes, upregulated CD11b on the cell surface, and improved NBT reduction activity. These results demonstrate that MDS-L cells ecopically expressing G-CSFR are induced to granulocytic differentiation upon exposure to G-CSF, and shed light on the molecular mechanisms of maturation arrest in MDS cells.
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PMID:Retrovirus-mediated gene transfer of granulocyte colony-stimulating factor receptor (G-CSFR) cDNA into MDS cells and induction of their differentiation by G-CSF. 1110 71

The CCAAT/enhancer binding protein alpha (C/EBPalpha) protein is essential for proper lung and liver function and granulocytic and adipose tissue differentation. It was hypothesized that abnormalties in C/EBPalpha function contribute to the development of malignancies in a variety of tissues. To test this, genomic DNA from 408 patient samples and 5 cell lines representing 11 different cancers was screened for mutations in the C/EBPalpha gene. Two silent polymorphisms termed P1 and P2 were present at frequencies of 13.5% and 2.2%, respectively. Of the 12 mutations detected in 10 patients, silent changes were identified in one nonsmall cell lung cancer, one prostate cancer, and one acute myelogenous leukemia (AML) subtype M4. The 9 remaining mutations were detected in 1 of 92 (1.1%) myelodysplastic syndrome (MDS) samples and 6 of 78 (7.7%) AML (AML-M2 and AML-M4) samples. Some mutations truncated the predicted protein with loss of the DNA-binding (basic region) and dimerization (leucine zipper [ZIP]) domains by either deletions or nonsense codons. Also, inframe deletions or insertions in the fork region located between the leucine zipper and basic region, or within the leucine zipper, disrupted the alpha-helical phase of the bZIP domain. The inframe deletion and insertion mutations abrogated the transcriptional activation function of C/EBPalpha on the granulocyte colony-stimulating factor receptor promoter. These mutants localized properly to the nucleus, but were unable to bind to the C/EBP site in the promoter and did not possess dominant-negative activity. The mutations in the MDS patient and one AML-M2 patient were biallelic, indicating a loss of C/EBPalpha function. These results suggest that mutation of C/EBPalpha is involved in specific subtypes of AML and in MDS, but may occur rarely in other types of leukemias or nonhematologic malignancies.
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PMID:Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. 1183 Apr 84

Recent studies have shown that point mutations in granulocyte colony-stimulating factor receptor (G-CSFR) are involved in the pathogenesis of severe congenital neutropenia (SCN) and in the transformation of SCN to acute myelogenous leukemia (AML). It is reasonably speculated that the abnormalities in the signal transduction pathways for G-CSF could be partly responsible for the pathogenesis and the development to AML in patients with myelodysplastic syndromes (MDS). Therefore, we investigated the structural and functional abnormalities of the G-CSFR in 14 patients with MDS and 10 normal subjects. In in vitro colony forming assay, MDS samples showed reduced response to growth factors. However, G-CSF, but not GM-CSF and IL-3, enhanced clonal growth in three cases of high risk patients with MDS (RAEB, RAEB-t, and MDS having progressed to acute myeloid leukemia (AML)) and one low risk patient (RA). Eight out of 14 patients including above 4 patients demonstrated a common deletion of the G-CSFR cDNA; a deletion of three nucleotides (2128-2130) in the juxtamembrane domain of the G-CSFR, which resulted in a conversion of Asn(630)Arg(631) to Lys(630). To assess the functional activities of this deletion in the G-CSFR isoform, a mutant with the same three-nucleotide deletion was constructed by site-directed mutagenesis. FDCP-2 cells expressing the G-CSFR isoform responded to G-CSF, and exhibited proliferative responses than did those cells having wild-type G-CSFR. Moreover, these isoforms showed prolonged activation of STAT3 in response to G-CSF than did the wild-type. These results suggest that the deletion in the juxtamembrane domain of the G-CSFR gives a growth advantage to abnormal MDS clones and may contribute to the pathogenesis of MDS.
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PMID:Novel variant isoform of G-CSF receptor involved in induction of proliferation of FDCP-2 cells: relevance to the pathogenesis of myelodysplastic syndrome. 1201 28

CD34++ cells from 45 patients with myelodysplastic syndrome (MDS) and MDS-acute myeloid leukaemia (MDS-AML) were observed by flow cytometry for the expression of granulocyte colony-stimulating factor receptor (G-CSFR). Ten patients had a significantly reduced expression of G-CSFR. Late stages of disease showed a higher proportion of either high or low G-CSFR expression than earlier stages. In MDS refractory anaemia (RA), G-CSFR was inversely related to CD33 expression. Most patients (9/10) with low G-CSFR expression had neutropenia of the peripheral blood. Neutropenia was less common in the normal group, but also occurred in the high expression group. No neutrophil response was observed following G-CSF administration to MDS-AML patients (6/6) with low G-CSFR expression. In the high expression group, patients (3/3) showed a response to G-CSF while, in the normal group (1/2), the response was minor. In the normal- or high-receptor-expressing groups, the receptors were functionally active in terms of apoptosis but not proliferation and clonogenic growth, although no clear correlation to receptor expression was observed. The G-CSFR signal transduction pathway in the normal and high group was not deficient of messenger RNA for either janus kinases (Jaks) or signal transducers and activators of transcription (Stats). These findings suggest that the lowered expression of G-CSFR may cause neutropenia in MDS and MDS-AML patients and, therefore, may partially explain the neutropenia in myelodysplastic patients.
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PMID:Expression and functional analysis of granulocyte colony-stimulating factor receptors on CD34++ cells in patients with myelodysplastic syndrome (MDS) and MDS-acute myeloid leukaemia. 1267 Mar 33

Severe congenital neutropenia (SCN) is a hematopoietic disorder characterized by neutropenia in peripheral blood and maturation arrest of neutrophil precursors in bone marrow. Patients with SCN may evolve to have myelodysplastic syndrome or acute myelocytic leukemia. In approximately 20% of SCN cases, a truncation mutation is found in the cytoplasmic region of the granulocyte colony-stimulating factor receptor (G-CSFR). We then generated mice carrying murine wild-type G-CSFR and its mutants equivalent to truncations at amino acids 718 and 731 in human G-CSFR, those were reported to be related to leukemic transformation of SCN. Although numbers of peripheral white blood cells, red blood cells, and platelets did not differ among mutant and wild-type G-CSFR transgenic (Tg) mice, both of the mutant receptor Tg mice had one third of peripheral neutrophil cell counts compared with wild-type receptor Tg mice. The mutant receptor Tg mice also showed impaired resistance to the infection with Staphylococcus aureus. Moreover, bone marrow of these Tg mice had an increased percentage of immature myeloid cells, a feature of SCN. This maturation arrest was also observed in in vitro cultures of bone marrow cells of truncated G-CSFR Tg mice under G-CSF stimulation. In addition, clonal culture of bone marrow cells of the truncated G-CSFR Tg mice showed the hypersensitivity to G-CSF in myeloid progenitors. Our Tg mice may be useful in the analysis of the role of truncated G-CSFR in SCN pathobiology.
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PMID:Impaired neutrophil maturation in truncated murine G-CSF receptor-transgenic mice. 1267 95

We studied surface expression of granulocyte colony-stimulating factor receptor (G-CSFR) on CD34++ progenitor cells of myelodysplastic patients. Late stages of disease showed a higher proportion of high or low G-CSFR expression than early stages. Most of the patients with the low expression had neutropenia. Neutropenia was relatively less present in the normal group, but it reappeared in the high group. All the neutropenic patients in the high group showed response to G-CSF, while response in the normal group was minor. These findings suggest that lowered expression of G-CSFR leads to neutropenia in myelodysplastic patients. This article reviewed the knowledge of the G-CSFR and its role in the disorders of granulopoiesis, including myelodysplastic syndrome (MDS).
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PMID:Granulocyte colony-stimulating factor receptors on CD34++ cells in patients with myelodysplastic syndrome (MDS) and MDS-acute myeloid leukemia. 1537 Feb 43

The granulocyte colony-stimulating factor receptor (G-CSF-R) transmits signals for proliferation and differentiation of myeloid progenitor cells. Here we report on the identification of a rare single nucleotide polymorphism within its intracellular domain (G-CSF-R_Glu785Lys). Screening a cohort of 116 patients with primary myelodysplastic syndromes (MDS), de novo acute myeloid leukemia (AML) (84 patients), as well as 232 age- and sex-matched controls revealed a highly significant association of the G-CSF-R_785Lys allele with the development of high-risk MDS as defined by more than 5% bone marrow blasts (9.7% versus 0.9% in controls; P = .001; odds ratio [OR], 12.5; 95% confidence interval [CI], 2.4-58.9) or an International Prognostic Scoring System score of intermediate-2 or high (13.0% versus 0.9%; P < .001; OR, 14.0; 95% CI, 3.4-85.0). Functional analysis by retroviral transfer of G-CSF-R_785Lys into myeloid progenitor cells of G-CSF-R-deficient mice showed a significantly diminished colony-formation capacity after G-CSF stimulation as compared with cells transduced with the wild-type receptor. These results suggest that lifelong altered G-CSF response by the G-CSF-R_785Lys may render individuals susceptible to development of high-risk MDS.
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PMID:A functional single-nucleotide polymorphism of the G-CSF receptor gene predisposes individuals to high-risk myelodysplastic syndrome. 1564 19

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


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