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)

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

De novo epigenetic changes at histone and DNA level that affect gene transcription in cancer may be less random than we originally thought. Leukemia fusion proteins associated with specific chromosome translocations could mechanistically determine the epigenetic fate of specific target genes critical for normal hematopoiesis. This seems to be the case with AML1-MTG16, a fusion protein resulting from the t(16;21) translocation, a hallmark of therapy-related leukemia and myelodysplastic syndrome. Here we show that AML1-MTG16 blocks both myeloid differentiation and proliferation in the 32D/WT1-mouse myeloid cell line. These biological effects can be traced to the AML1 and MTG16 moieties of the fusion protein, respectively. Further, we show that AML1-MTG16 can induce epigenetic repressive changes at the histone and DNA level of the AML1 target gene Csf1r (c-fms), encoding the macrophage colony stimulating factor receptor. We observed that, concomitant with Csf1r downregulation, 32D/WT1 cells lost the ability to undergo myeloid differentiation in response to the granulocyte macrophage colony-stimulating factor (GM-CSF). Thus, there seems to be an association between AML1-MTG16-induced myeloid maturation block and epigenetic changes of a myeloid master gene.
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PMID:Myeloid maturation block by AML1-MTG16 is associated with Csf1r epigenetic downregulation. 1600 22

Mutations of the FLT3, c-KIT, c-FMS, KRAS, NRAS, BRAF and CEBPA genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal-transduction pathway are frequent in acute myeloid leukemia (AML). We examined 140 patients with therapy-related myelodysplasia or AML (t-MDS/t-AML) for point mutations of these seven genes. In all, 11 FLT3, two c-KIT, seven KRAS, eight NRAS and three BRAF mutations were identified in 29 patients (21%). All but one patient with a FLT3 mutation presented with t-AML (P=0.0002). Furthermore, FLT3 mutations were significantly associated with previous radiotherapy without chemotherapy (P=0.03), and with a normal karyotype (P=0.004), but inversely associated with previous therapy with alkylating agents (P=0.003) and with -7/7q- (P=0.001). RAS mutations were associated with AML1 point mutations (P=0.046) and with progression from t-MDS to t-AML (P=0.008). Noteworthy, all three patients with BRAF mutations presented as t-AML of M5 subtype with t(9;11)(p22;q23) and MLL-rearrangement (P=0.01). In t-AML RAS/BRAF mutations were significantly associated with a very short survival (P=0.017). Half of the patients with a mutation in the RTK/RAS-BRAF signal-transduction pathway (denoted 'class-I' mutations) simultaneously disclosed mutation of a hematopoietic transcription factor (denoted 'class-II' mutations) (P=0.046) suggesting their cooperation in leukemogenesis.
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PMID:Mutations of genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway in therapy-related myelodysplasia and acute myeloid leukemia. 1628 Oct 72

Although there has been significant progress in acute myeloid leukemia (AML) treatment in younger adults during the last decade, standard induction therapy still fails to induce remission in up to 40% of AML patients. Additionally, relapses are common in 50-70% of patients who achieve a complete remission, and only 20-30% of patients enjoy long-term disease-free survival. The natural history of myelodysplastic syndrome (MDS) is variable, with about half of the patients dying from cytopenic complications, and an additional 20-30% transforming to AML. The advanced age of the majority of MDS patients limits the therapeutic strategies often to supportive care. To address these shortcomings, much effort has been directed toward the development of novel treatment strategies that target the evolution and proliferation of malignant clones. Presented here is an overview of molecularly targeted therapies currently being tested in AML and MDS patients, with a focus on FMS-like tyrosine kinase 3 inhibitors, farnesyltransferase inhibitors, antiangiogenesis agents, DNA hypomethylation agents, and histone deacetylase inhibitors.
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PMID:Molecularly targeted therapies in myelodysplastic syndromes and acute myeloid leukemias. 1639 11

Myelodysplastic syndromes (MDS) are rare disorders in children. Molecular mechanisms underlying MDS in children are not yet completely understood. Considering the role of FMS and TP53 gene mutations in adult MDS patients, we analyzed mutations of these genes in a cohort of 35 children with MDS. Single-strand conformation polymorphism polymerase chain reaction analysis performed on FMS codon 969 and TP53 exons 5-9 showed no mutations in the analyzed sequences. Our results suggest that molecular mechanisms of MDS evolution in children are different from those in adults.
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PMID:Lack of TP53 and FMS gene mutations in children with myelodysplastic syndrome. 1663 74

Tandutinib (MLN518/CT53518) is a novel quinazoline-based inhibitor of the type III receptor tyrosine kinases: FMS-like tyrosine kinase 3 (FLT3), platelet-derived growth factor receptor (PDGFR), and KIT. Because of the correlation between FLT3 internal tandem duplication (ITD) mutations and poor prognosis in acute myelogenous leukemia (AML), we conducted a phase 1 trial of tandutinib in 40 patients with either AML or high-risk myelodysplastic syndrome (MDS). Tandutinib was given orally in doses ranging from 50 mg to 700 mg twice daily The principal dose-limiting toxicity (DLT) of tandutinib was reversible generalized muscular weakness, fatigue, or both, occurring at doses of 525 mg and 700 mg twice daily. Tandutinib's pharmacokinetics were characterized by slow elimination, with achievement of steady-state plasma concentrations requiring greater than 1 week of dosing. Western blotting showed that tandutinib inhibited phosphorylation of FLT3 in circulating leukemic blasts. Eight patients had FLT3-ITD mutations; 5 of these were evaluable for assessment of tandutinib's antileukemic effect. Two of the 5 patients, treated at 525 mg and 700 mg twice daily, showed evidence of antileukemic activity, with decreases in both peripheral and bone marrow blasts. Tandutinib at the MTD (525 mg twice daily) should be evaluated more extensively in patients with AML with FLT3-ITD mutations to better define its antileukemic activity.
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PMID:Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. 1690 53

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis and risk for evolving to acute leukemia. Some molecular abnormalities related to acute myeloid leukemia (AML) transformation have been reported, such as FLT3 (FMS-like tyrosine kinase 3) mutations. FLT3, a member of the class 3 receptor tyrosine kinase family, mediates stem cell proliferation and differentiation, and its mutations, internal tandem duplication (ITD) and Asp835, have been reported in rare MDS patients. We studied FLT3 ITD, prospectively, in 50 MDS patients at diagnosis, at 6 and 12 months follow-up, and at any other time-point if AML transformation was detected. FLT3 ITD was not observed at diagnosis, but during follow-up the mutation was present in 2 of 50 patients (4%). Of these, one case exhibited FLT3 ITD at the end of the 6 months of follow-up in approximately 8% of bone marrow cells; this case evolved into AML at 8 months, at which time FLT3 ITD was present in approximately 85% of bone marrow cells. The other case exhibited FLT3 ITD in 68% of bone marrow cells at 7 months, precisely at the time of AML transformation. Although rare in MDS, FLT3 ITD is associated with a high probability of evolution to AML.
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PMID:FLT3 internal tandem duplication during myelodysplastic syndrome follow-up: a marker of transformation to acute myeloid leukemia. 1850 25

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

Acute myeloid leukemia (AML) accounts for approximately 80% of acute leukemias diagnosed in adults. The elderly are disproportionately affected by AML, as 35% of newly diagnosed patients are aged >or=75 and the median age at diagnosis is 67. Elderly individuals also respond less well to standard chemotherapy than do younger individuals, as reflected by lower complete remission and relapse-free survival rates in major clinical trials. A higher prevalence of comorbid conditions as well as the unique biological features of elderly AML patients account for the relatively poor response to therapy observed in this population. Compared with AML in younger individuals, for example, AML in the elderly more often emerges from a preceding myelodysplastic syndrome and is more frequently associated with poor-prognosis karyotypes such as 5q- or 7q-. The introduction of novel therapies over the past decade has already altered the treatment paradigm of elderly individuals with AML. The first of these to emerge was gemtuzumab ozogamicin. Other agents are currently under evaluation in clinical trials, including inhibitors of multidrug resistance, farnesyltransferase inhibitors, novel nucleoside analogues, and inhibitors of the FMS-like tyrosine kinase-3. This review describes the biological features of AML in the elderly and summarizes both the current and emerging strategies for the treatment of this disease in older individuals.
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PMID:Current and emerging strategies for the management of acute myeloid leukemia in the elderly. 1892 30

This study was aimed to detect the ratio of CD34+ cells in bone marrow mononuclear cells (BMMNCs) and the expression rate of G(M)-CSFR on CD34+ cells in bone marrow of the patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS). The ratio of CD34+ cells in BMMNCs and the expression rate of G(M)-CSFR on cells of 27 AA patients, 45 MDS patients and 20 controls were detected by flow cytometry (FCM). The results showed that the ratio of CD34+ cells in BMMNCs of AA patients reduced and was significantly different from controls (p<0.05), the ratio of CD34+ cells in MDS patients elevated and was significantly different from controls (p<0.05). Compared with controls and MDS-RA patients, the ratio of CD34+ cells in MDS-RAEB patients significantly elevated (p<0.05), but there was no significant difference between MDS-RA patients and controls (p>0.05). The ratio of CD34+ cells in MDS-RA patients was significantly higher than that in AA patients (p<0.05). There was no significant difference in expression rate of G-CSFR on CD34+ cells between AA patients and controls, MDS patients and controls, AA patients and MDS patients, MDS-RA patients and MDS-RAEB patients (p>0.05). The expression rate of GM-CSFR in MDS patients was significantly higher than that in AA patients and controls (p<0.05), but there was no significant difference between AA patients and controls, MDS-RA patients and MDS-RAEB patients (p>0.05). In AA patients, the ratio of CD34+ cells in BMMNCs was less than 0.1% accounts for 6/8 SAA patients, compared with 2/19 in CAA (p<0.05). There was no correlation between the expression rate of either G-CSFR or GM-CSFR and neutrophil count at diagnosis (r=0.058 and r=0.044). In MDS patients, there was no correlation between bone marrow CD34+ cells ratio and peripheral neutrophil count at diagnosis (r=-0.335). And there was no correlation between the expression of either G-CSFR or GM-CSFR and neutrophil count on diagnosis (r=0.064 and r=0.051). It is concluded the detection of CD34+ cells and their surface expression rate of G(M)-CSFR in AA and MDS is useful in diagnosis and differential diagnosis of these two diseases.
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PMID:[Expression of G-CSF and GM-CSF receptors on CD34 positive cells in aplastic anemia and myelodysplastic syndrome patients and its significance]. 1909 33


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