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)

To determine whether patients with acquired asplastic anemia (AA) exhibit clonal hematopoiesis, we used restriction fragment length polymorphisms of the X-linked genes phosphoglycerate kinase (PGK1) and hypoxanthine phosphoribosyltransferase (HPRT) and the X-linked probe M27 beta. Of the 19 female patients studied, 18 (95%) patients were informative for at least one marker. Of these, eight patients (42%) were heterozygous for PGK1, two (11%) for HPRT, and 16 (84%) for M27 beta. In 13 (72%) patients, a monoclonal pattern was found. Analysis of purified cell suspensions of four of these patients showed that both myeloid and lymphoid cells were of monoclonal origin, indicating the involvement of an early stem cell. The four patients who were studied at presentation all showed a monoclonal pattern. One of these patients showed a spontaneous recovery despite persistent clonal hematopoiesis. The presence of either clonal or polyclonal hematopoiesis did not show a correlation with the response to antithymocyte globulin (ATG) treatment. A relapse after ATG was also seen in a patient exhibiting polyclonal hematopoiesis. Conversely, a monoclonal pattern did not preclude the occurrence of a partial or complete response to ATG. Other potential markers to study clonality, including cytogenetic abnormalities or point mutations of the N-ras protooncogene, were not found in any of the patients. It is concluded that patients with AA may exhibit clonal hematopoiesis. The significance with respect to evolution to disorders with clonal hematopoiesis like paroxysmal nocturnal hemoglobinuria, myelodysplasia, and acute leukemia remains to be determined.
Blood 1991 Dec 15
PMID:Clonal hematopoiesis in patients with acquired aplastic anemia. 163 35

The retinoblastoma-susceptibility (Rb) gene is an antioncogene that is frequently altered in retinoblastomas, sarcomas, and some epithelial tumors. We examined the structure of the Rb gene by Southern blotting in 215 cases of leukemias and lymphomas of diverse phenotype and in 15 leukemic cell lines. In selected cases Rb protein expression was examined with specific monoclonal antibodies. Structural abnormalities of the Rb gene with absent protein expression were frequent in all types of human acute leukemia, but were particularly common (27% incidence) in M4 and M5 myeloid leukemia with monocytic differentiation and in Philadelphia chromosome (Ph1)-positive leukemia of lymphoid phenotype (11% to 29% incidence). Changes in Rb were observed early in the transition to acute leukemia in cases of myelodysplastic syndrome and in the accelerated phase of chronic myelocytic leukemia in transition to blast crisis. In one case, molecular changes in Rb could be correlated with leukemia remission and relapse. We conclude that the Rb antioncogene is commonly involved in the evolution of human acute leukemias, particularly in those of a monocytic phenotype and in lymphoid leukemia in which there is an antecedent alteration of the Ph1 chromosome.
Blood 1991 Dec 15
PMID:Abnormalities of the retinoblastoma gene in the pathogenesis of acute leukemia. 168 97

We have used X-linked restriction fragment length polymorphism (RFLP)-methylation and gene deletion analyses to investigate the nature of the progenitor cell of origin in the myelodysplastic syndromes (MDS). Gene deletion studies were performed on the granulocyte and T-lymphocyte fractions of six women with refractory anaemia (RA) and either a partial deletion of the long arm of chromosome 5 (5q-) or monosomy 7. All six showed gene loss in the granulocyte but not the T-lymphocyte fractions, indicating monoclonality of the granulocytes but not the T-lymphocytes. In order to further investigate this finding, we subsequently performed X-RFLP-methylation studies using the probe M27 beta, and also a probe for the phosphoglycerate kinase (PGK) gene. These studies have confirmed the monoclonality of the granulocytes and the polyclonality of the T-lymphocytes in these cases. Our findings suggest that in this group of patients with MDS the T-lymphocytes were not involved in the disorder, and furthermore, in the one case where B-lymphocytes were also available, that the progenitor cell of origin was restricted to the myeloid lineage.
Br J Haematol 1991 Dec
PMID:Clonality of cell populations in refractory anaemia using combined approach of gene loss and X-linked restriction fragment length polymorphism-methylation analyses. 168 26

Low dose 5-azacytidine was administered to 11 patients with acute myeloid leukemia (AML) in hopes of achieving complete remissions by inducing differentiation of leukemic blasts. The patient population included both patients who had received no prior therapy (two patients), as well as patients refractory to primary therapy (five patients) and patients who had relapsed after achieving complete remission (four patients). Both previously untreated patients had a history of myelodysplastic syndrome, and two of the primarily refractory patients had leukemia following chemotherapy for other malignancies. The median age was 55 years (range 36-78 years). Twenty-one courses of 5-azacytidine were administered as 7-day continuous infusions at a dose of 75 mg/m2/day. Significant nonhematologic toxicity was not observed. No patient had a response as defined by bone marrow remission or improvement in transfusion requirement for red blood cells or platelets. Although some patients developed bone marrow hypocellularity (six courses in five patients), none became aplastic, and eight courses in six patients were associated with increased bone marrow cellularity percentage of blasts. Five courses in three patients were inevaluable (one central nervous system hemorrhage, one central nervous system leukemia, three courses in one patient who refused bone marrow aspiration). It is unlikely that low dose 5-azacytidine will be of benefit to patients with AML, and there was no evidence of clinically significant induction of differentiation noted.
Leukemia 1990 Dec
PMID:Low dose 5-azacytidine is ineffective for remission induction in patients with acute myeloid leukemia. 170 Aug 39

We investigated the effects of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) therapy on the natural killer (NK) cell lineage in patients with aplastic anemia and myelodysplastic syndrome. Selected bone marrow (BM) cells were prepared by the elimination of nylon wool-adherent cells and mature T and NK cells from BM cells. The frequency of BM NK progenitors relative to BM cells selected was significantly decreased 4 weeks after the start of rhGM-CSF therapy (P less than .01), while the peripheral blood NK cell count and NK activity were also significantly decreased (P less than .05). A return to the pretreatment levels was seen 4 weeks after the cessation of treatment in all cases. No suppressive effect was noted in the patients who received rhG-CSF therapy. These results suggest that rhGM-CSF therapy suppresses the generation of NK cells from human BM NK progenitors.
Blood 1991 Dec 15
PMID:Inhibitory effect of granulocyte-macrophage colony-stimulating factor therapy on the generation of natural killer cells. 172 Jul

Relapse continues to be a problem after bone marrow transplantation (BMT) for hematologic malignancies, particularly in recipients of autologous or T-cell-depleted allogeneic grafts and in patients with advanced disease. Interferon (IFN) has shown antiproliferative activity in several malignant hematologic diseases and potentially may be of benefit when administered early after BMT when the number of residual cells is minimal. We tested in a phase I study the maximum tolerated daily dose of recombinant IFN alpha-2b in patients who had received a transplant for a disease at high risk for relapse (acute myeloid leukemia or non-Hodgkin's lymphoma beyond first remission, advanced myelodysplastic syndrome, acute lymphoblastic leukemia at any stage, chronic myeloid leukemia in accelerated or blast phase. Recombinant IFN alpha-2b was started at a dose of 0.5 x 10(6) IU/m2 and escalated by 0.5 x 10(6) IU/m2 in groups of three or four patients. The intention was to administer IFN as soon as stable engraftment after BMT was achieved (defined as an absolute neutrophil count of greater than 2.0 x 10(9)/L and platelet count greater than 100 x 10(9)/L for 5 consecutive days) and continued for 2 months. A total of 14 patients were enrolled after autologous (n = 3) or allogeneic (n = 11) BMT. Dose-limiting toxicity was myelosuppression. Significant (grade 2 to 4) neutropenia and thrombocytopenia led to discontinuation or dose reduction in five of eight patients receiving 1.5 x 10(6) or 2 x 10(6) IU/m2 IFN. Mild to moderate (grade 1 or 2) anorexia, weight loss, and fatigue occurred in the majority of patients independent of the IFN dose. De novo acute GVHD responsive to steroid treatment developed in 3 of 11 allograft recipients. Natural killer (NK) cell function was low before IFN treatment and was not improved with the cytokine. Conversely, interleukin-2-activated NK cells showed normal function even before starting IFN and no change was seen during IFN treatment. Clonogenic hematopoietic progenitor studies showed depression of all progenitor lines (colony-forming unit [CFU]-granulocyte, erythroid, monocyte, megakaryocyte, CFU granulocyte-macrophage, burst-forming unit-erythroid) by IFN at all dose levels except at 0.5 x 10(6) IU/m2. Considering this result and the incidence and severity of marrow depression seen at doses greater than 1.0 x 10(6) IU/m2, we would consider this the maximum dose safely tolerated if IFN alpha-2b is administered in this setting for a prolonged course on a daily basis.
Blood 1991 Dec 15
PMID:Treatment with recombinant interferon (alpha-2b) early after bone marrow transplantation in patients at high risk for relapse [corrected]. 174 91

In an effort to overcome bone marrow failure in myelodysplastic syndrome (MDS), we have investigated recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) in phase I-II clinical trials. Although these agents partially increased peripheral blood granulocyte counts, their effect on other hematopoietic lineages was generally sporadic. Since in vitro analysis and in vivo studies in primates indicate that GM-CSF and IL-3 synergistically enhance hematopoietic stem cell proliferation, we evaluated their combined effect on marrow progenitors obtained from ten MDS patients. When used singly, each growth factor stimulated replication of granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) colony-forming cells in a dose-dependent fashion. When colony-stimulating activity was compared at concentrations that maximally amplified individual MDS patients' colony numbers, IL-3 was a more potent stimulant in some patients and GM-CSF in others. When used in combination, IL-3 plus GM-CSF was more effective than each growth factor by itself in five of six patients. Our data indicate that the MDS hematopoietic progenitor stimulatory effect of these growth factors varies from patient to patient. However, the combination of GM-CSF and IL-3 appears to be more potent than the individual molecules in the majority of patients.
Ann Hematol 1991 Dec
PMID:Granulocyte-macrophage colony-stimulating factor and interleukin-3 in combination: a potent and consistent myelodysplastic syndrome bone marrow stimulant in vitro. 175 90

Three patients, one with Philadelphia (Ph) chromosome positive chronic myelocytic leukemia (CML) and two with primary acquired myelodysplastic syndromes (MDS), have been identified to have a t(3;21)(q26;q22). In the patient with CML, the t(3;21) was detected only in the blast phase. The t(3;21) as the sole abnormality appeared at presentation of MDS [refractory anemia with excess blasts (RAEB)] in one patient and remained as such when progression to RAEB in transformation (RAEB-t) occurred. The other patient with MDS had the t(3;21), in addition to other changes, during the progression of the disease. Thus, t(3;21) may characterize myeloid crises of clonal hematopoietic stem cell disorders (HSCD) and indicates a poor prognosis. As a primary cytogenetic event it may be also involved in the genesis of myelodysplasia with subsequent leukemic transformation.
Cancer Genet Cytogenet 1991 Dec
PMID:Translocation (3;21) characterizes crises in myeloid stem cell disorders. 175 92

We have examined p53 alleles in 151 DNAs from patients with myelodysplastic syndrome using single-strand conformation polymorphism analysis of polymerase chain reaction products. We focused our study on the four highly conserved regions of the p53 gene and detected five patients with aberrantly migrating fragments. We confirmed the putative mutation in each case by direct sequencing analysis. Of these five patients, three had chromosome 17 monosomy associated with p53 mutation, one patient showed one mutated p53 allele and one wild-type allele, and the last patient demonstrated only the mutant allele, suggesting a homozygous state. Unlike many other types of human cancers, point mutations in the p53 tumor-suppressor gene appear to be a rare event in myelodysplastic syndromes.
Oncogene 1991 Dec
PMID:Mutations in the p53 gene in myelodysplastic syndromes. 176 71

We applied DAPI (4',6-diamidino-2-phenylindole) staining to the determination of nuclear DNA content in single megakaryocytes in 12 normal subjects and 12 patients with myelodysplastic syndrome (MDS). After the megakaryocytes had been identified on Wright-Giemsa stained smear and classified according to modified Feinendegen's classification, they were photographed. Then Wright-Giemsa stain was removed by immersion in 50% ethanol at 37 degrees C for 1 h and 100% methanol at 37 degrees C for 1 h. The specimens were then stained with DAPI solution (DAPI 0.01 mg/ml, pH 7.4 Tris-EDTA-2Na buffer solution and 0.01 M 2-mercaptoethylamine hydrochloride mixed at the ratio of 0.5:98.5:1.0) for more than 30 min. The amount of nuclear DNA in the previously identified megakaryocytes was measured by microcytofluorometry. The maximum population of megakaryocytes ploidy was in 16N in normal subjects, 8N in 10/12 MDS patients, and 4N in the remaining two patients. These findings suggest impairment of the development of the megakaryocytes nucleus in the MDS patients.
Br J Haematol 1991 Dec
PMID:Shift in the megakaryocyte ploidy in MDS patients: microcytofluorometry with DAPI staining after destaining of Wright-Giemsa stain. 177 76


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