Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark), used extensively for the management of hemophilia patients with inhibitors, has also been shown to be effective in the treatment of severe bleeding episodes and for coverage of surgical procedures in patients with platelet disorders. Cases include seven patients with congenital platelet disorders [Glanzmann thrombasthenia (n = 5), Bernard-Soulier syndrome (n = 1), platelet type (pseudo-) von Willebrand disease (n = 1)] and two patients with acquired thrombocytopathy associated with myelodysplastic syndrome and uremia. The clinical efficacy of rFVIIa in functional platelet disorders has been reported as good or excellent, although some cases of ineffectiveness exist. The agent is well tolerated with a single published case of thromboembolism as a postoperative complication. In addition to these reported cases, there are others that remain unreported and unpublished. An International Registry on Recombinant Factor VIIa and Congenital Platelet Disorders (forms in Appendix 1) has been established to obtain more safety and efficacy data on patients with congenital platelet disorders treated with NovoSeven. Analysis of data from this larger population will allow better comprehension of the role of NovoSeven in these disorders, and assist in the design of formal studies to address issues associated with the treatment of these disorders.
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PMID:Recombinant activated factor VII (NovoSeven) treatment of platelet-related bleeding disorders. International Registry on Recombinant Factor VIIa and Congenital Platelet Disorders Group. 1085 May 67

Somatically acquired point mutations of AML1/RUNX1 gene have been recently identified in rare cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Moreover, germ line mutations of AML1 were found in an autosomal dominant disease, familial platelet disorder with predisposition to AML (FPD/AML), suggesting that AML1 mutants, as well as AML1 chimeras, contribute to the transformation of hematopoietic progenitors. In this report, we showed that AML1 point mutations were found in 6 (46%) of 13 MDS patients among atomic bomb (A-bomb) survivors in Hiroshima. Unlike acute or chronic leukemia patients among A-bomb survivors, MDS patients exposed relatively low-dose radiation and developed the disease after a long latency period. AML1 mutations also were found in 5 (38%) of 13 therapy-related AML/MDS patients who were treated with alkylating agents with or without local radiation therapy. In contrast, frequency of AML1 mutation in sporadic MDS patients was 2.7% (2 of 74). Among AML1 mutations identified in this study, truncated-type mutants lost DNA binding potential and trans-activation activity. All missense mutations with one exception (Gly42Arg) lacked DNA binding ability and down-regulated the trans-activation potential of wild-type AML1 in a dominant-negative fashion. The Gly42Arg mutation that was shared by 2 patients bound DNA even more avidly than wild-type AML1 and enhanced the trans-activation potential of normal AML1. These results suggest that AML1 point mutations are related to low-dose radiation or alkylating agents and play a role distinct from that of leukemogenic chimeras as a result of chromosomal translocations caused by sublethal radiation or topoisomerase II inhibitors.
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PMID:Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia. 1239 79

AML1/RUNX1, located on chromosome band 21q22, is one of the most important hematopoietic transcription factors. AML1 is frequently affected in leukemia and myelodysplastic syndrome with 21q22 translocations. Recently, AML1 mutations were found in adult hematologic malignancies, especially acute myeloid leukemia (AML)-M0 or leukemia with acquired trisomy 21, and familial platelet disorder with a predisposition toward AML. Through the use of polymerase chain reaction-single-strand conformation polymorphism analysis, we examined the AML1 gene for mutations in 241 patients with pediatric hematologic malignancies, and we detected AML1 mutations in seven patients (2.9%). Deletion was found in one patient, and point mutations in four patients, including three missense mutations, two silent mutations, and one mutation within an intron resulting in an abnormal splice acceptor site. All of the mutations except for one were heterozygous. Mutations within the runt domain were found in six of seven patients. Six of seven patients with AML1 mutations were diagnosed with AML, and one had acute lymphoblastic leukemia. In three of these seven patients, AML evolved from other hematologic disorders. AML1 mutations were found in two of four AML-M0 and two of three patients with acquired trisomy 21. Patients with AML1 mutations tended to be older children. Three of four patients with AML1 mutations who received stem cell transplantation (SCT) are alive, whereas the remaining three patients with mutations without SCT died. These results suggest that AML1 mutations in pediatric hematologic malignancies are infrequent, but are possibly related to AML-M0, acquired trisomy 21, and leukemic transformation. These patients may have a poor clinical outcome.
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PMID:AML1/RUNX1 mutations are infrequent, but related to AML-M0, acquired trisomy 21, and leukemic transformation in pediatric hematologic malignancies. 1287 80

Embryonic development of multilineage hematopoiesis requires the precisely regulated expression of lineage-specific transcription factors, including AML-1 (encoded by Runx1; also known as CBFA-2 or PEBP-2alphaB). In vitro studies and findings in human diseases, including leukemias, myelodysplastic syndromes and familial platelet disorder with predisposition to acute myeloid leukemia (AML), suggest that AML-1 has a pivotal role in adult hematopoiesis. However, this role has not been fully uncovered in vivo because of the embryonic lethality of Runx1 knockout in mice. Here we assess the requirement of AML-1/Runx1 in adult hematopoiesis using an inducible gene-targeting method. In the absence of AML-1, hematopoietic progenitors were fully maintained with normal myeloid cell development. However, AML-1-deficient bone marrow showed inhibition of megakaryocytic maturation, increased hematopoietic progenitor cells and defective T- and B-lymphocyte development. AML-1 is thus required for maturation of megakaryocytes and differentiation of T and B cells, but not for maintenance of hematopoietic stem cells (HSCs) in adult hematopoiesis.
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PMID:AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis. 1499 Oct 45

Familial platelet disorder with propensity to acute myelogenous leukemia, or FPD/AML (OMIM #601399), is a rare autosomal dominant condition, with only 12 families reported. It is characterized by qualitative and quantitative platelet defects and predisposition to the development of myeloid malignancies. Causal mutations have been identified in the RUNX1 gene (also known as AML1, CBFA2) in the 11 families so far analyzed. RUNX1 is a gene frequently involved in the pathogenesis of sporadic leukemia and myelodysplastic syndromes, through acquired chromosome rearrangements and point mutations. We report an Italian family with three members affected with FPD/AML, two sibs and their father, who developed myelodysplastic syndromes (which in one subsequently evolved into AML). Direct sequencing and polymorphisms haplotype analysis of the region of chromosome 21 where RUNX1 is mapped demonstrated that FPD/AML in this family was not caused by any mutation of the RUNX1 gene, thus providing evidence for the genetic heterogeneity of this disorder. Cytogenetic studies showed monosomy 7 in the marrow of all the three affected subjects, as well as an independent clone with trisomy 8 in the father. The importance of mutator effects in the pathogenesis of familial myeloid malignancies characterized by relevant chromosome changes, in the presence or absence of an underlying Mendelian disorder, has already been suggested. Our results and a review of the cytogenetic literature led us to postulate that mutations also causing FPD/AML may have a mutator effect that could give origin to myelodysplastic syndromes and acute myeloid leukemias through acquired chromosome changes.
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PMID:Familial platelet disorder with propensity to acute myelogenous leukemia: genetic heterogeneity and progression to leukemia via acquisition of clonal chromosome anomalies. 1513 96

The RUNX1/AML1 gene is the most frequent target for chromosomal translocation in leukemia. In addition, recent studies have demonstrated point mutations in the RUNX1 gene as another mode of genetic alteration in development of leukemia. Monoallelic germline mutations in RUNX1 result in familial platelet disorder predisposed to acute myelogenous leukemia (FPD/AML). Sporadic point mutations are frequently found in three leukemia entities: AML M0 subtype, MDS-AML, and secondary (therapy-related) MDS/AML. Therapy-related leukemias resulting from anticancer treatments are not uncommon, and the incidence of RUNX1 point mutations appears comparable to the incidence of the t(8;21) AML M2 subtype and the inv(16) AML M4Eo subtype. Half of the point mutations in M0 cases are biallelic, although the frequency varies with ethnicity. Most of the RUNX1 mutations are clustered in the Runt domain and result in defective DNA binding but active beta-subunit binding, which is consistent with three-dimensional structural findings and may explain the dominant inhibitory effects. Unlike the classical tumor suppressor genes requiring biallelic inactivation, haploinsufficient RUNX1 is apparently leukemogenic. However, RUNX1 abnormalities per se are insufficient to cause full-blown leukemia. Intensive investigation of cooperating genetic alterations should elucidate leukemic mechanisms.
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PMID:Point mutations in the RUNX1/AML1 gene: another actor in RUNX leukemia. 1515 85

The occurrence of a thrombocytopathy concomitantly to the development of a malignant haemopathy has been reported for some time, but little is known about the mechanism(s) involved in the platelet dysfunction. Platelet glycoprotein VI (GPVI) has now been identified as a principal platelet receptor for collagen. In this paper, we report the cases of two patients with a myelodysplasia and a B lymphopathy, respectively, who presented with thrombocytopathy in relation to a defective GPVI-mediated platelet reactivity to collagen. Thus, with regard to the different steps of adhesion, activation secretion or aggregation, patients' platelet responses to collagen and to the GPVI specific agonists, collagen related peptide (CRP) or convulxin were null or dramatically impaired. Platelet responses to other agonists ADP, TRAP, Arachidonic acid were normal or showed only a moderate decrease. GPVI content was repeatedly normal, and binding of specific ligands, such as convulxin, satisfactory. Nevertheless, specific activating monoclonal antibodies and convulxin failed to induce platelet secretion; collagen, CRP or convulxin were unable to provoke calcium mobilisation. Furthermore, using a perfusion chamber model, we showed that ex vivo collagen-induced thrombi formation was very impaired. Taken together, these data provide evidence, for the first time, of an acquired defect in GPVI-mediated platelet reactivity to collagen, which reflects data observed in constitutional GPVI deficiencies, in two patients with malignant haemopathies.
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PMID:Defective collagen-induced platelet activation in two patients with malignant haemopathies is related to a defect in the GPVI-coupled signalling pathway. 1563 May 3

AML1 (RUNX1) encodes a DNA-binding subunit of the CBF transcription factor family and is required for the establishment of definitive hematopoiesis. AML1 is one of the most frequently mutated genes associated with human acute leukemia, suggesting that genetic alterations of the gene contribute to leukemogenesis. Here, we report the analysis of mice carrying conditional AML1 knockout alleles that were inactivated using the Cre/loxP system. AML1 was deleted in adult mice by inducing Cre activity to replicate AML1 deletions found in human MDS, familial platelet disorder and rare de novo human AML. At a latency of 2 months after induction, the thymus was reduced in size and frequently populated by immature double negative thymocytes, indicating defective T-lymphocyte maturation, resulting in lymphatic diseases with 50% penetrance, including atypical hyperplasia and thymic lymphoma. Metastatic lymphomas to the liver and the meninges were observed. Mice also developed splenomegaly with an expansion of the myeloid compartment. Increased Howell-Jolly body counts indicated splenic hypofunction. Thrombocytopenia occurred due to immaturity of mini-megakaryocytes in the bone marrow. Together with mild lymphocytopenia in the peripheral blood and increased fractions of immature cells in the bone marrow, AML1 deficient mice display features of a myelodysplastic syndrome, suggesting a preleukemic state.
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PMID:AML1 deletion in adult mice causes splenomegaly and lymphomas. 1624 65

Monoallelic RUNX1 mutations cause familial platelet disorder with predisposition for acute myelogenous leukemia (FPD/AML). Sporadic mono- and biallelic mutations are found at high frequencies in AML M0, in radiation-associated and therapy-related myelodysplastic syndrome and AML, and in isolated cases of AML M2, M5a, M3 relapse, and chronic myelogenous leukemia in blast phase. Mutations in RUNX2 cause the inherited skeletal disorder cleidocranial dysplasia (CCD). Most hematopoietic missense mutations in Runx1 involve DNA-contacting residues in the Runt domain, whereas the majority of CCD mutations in Runx2 are predicted to impair CBFbeta binding or the Runt domain structure. We introduced different classes of missense mutations into Runx1 and characterized their effects on DNA and CBFbeta binding by the Runt domain, and on Runx1 function in vivo. Mutations involving DNA-contacting residues severely inactivate Runx1 function, whereas mutations that affect CBFbeta binding but not DNA binding result in hypomorphic alleles. We conclude that hypomorphic RUNX2 alleles can cause CCD, whereas hematopoietic disease requires more severely inactivating RUNX1 mutations.
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PMID:Disease mutations in RUNX1 and RUNX2 create nonfunctional, dominant-negative, or hypomorphic alleles. 1729 Feb 19

Familial occurrence of myelodysplasia (MDS) and/or acute myeloid leukaemia (AML) is rare but can provide a useful resource for the investigation of predisposing mutations in these myeloid malignancies. To date, examination of families with MDS/AML has lead to the detection of two culprit genes, RUNX1 and CEBPA. Germline mutations in RUNX1 result in familial platelet disorder with propensity to myeloid malignancy and inherited mutations of CEBPA predispose to AML. Unfortunately, the genetic cause remains obscure in most other reported pedigrees. Further insight into the molecular mechanisms of familial MDS/AML will require awareness by clinicians of new patients with relevant family histories.
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PMID:Familial myelodysplasia and acute myeloid leukaemia--a review. 1817 51


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