UMLS:C0026986 - FACTA Search

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Query: UMLS:C0026986 (myelodysplastic syndrome)
14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The progenitor cells of myelodysplastic syndrome (MDS) are thought to undergo a multistep process during their transformation into overt acute leukemia. In this study, the role of mutation of the KIT gene in the extracellular membrane, juxtamembrane and tyrosine kinase domains was investigated in 75 patients with MDS or MDS-derived leukemia (MDS-AML). Mutation was detected in 2 of 15 (13.3%) patients with refractory anemia with excess blasts transformation (RAEB-T), in 1 of 15 (6.6%) patients with chronic myelomonocytic leukemia (CMML), and in 5 of 26 (19.2%) patients with MDS-AML. However, no mutation was found in any of the nine patients with refractory anemia (RA) or the 10 patients with refractory anemia with excess blasts (RAEB). Of the mutations, five patients had changes at the same codon in tyrosine kinase domain, Asp816, while the remainder had unique mutations. These observations suggest that KIT gene mutations identified in the advanced stage of MDS, and genetic abnormality in the KIT gene, particularly at codon 816, might be additional events that contribute to the progression of MDS to AML.
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PMID:Mutational analysis of the KIT gene in myelodysplastic syndrome (MDS) and MDS-derived leukemia. 1653 29

PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase and the c-kit protein tyrosine kinase. The objective of this Phase I study was to evaluate the safety, tolerability, biologic activity and pharmacologic profile of PTK/ZK administered orally, twice daily, on a continuous dosing schedule in patients with primary refractory or relapsed acute myeloid leukemia (AML), secondary AML, poor-prognosis de novo AML or advanced myelodysplastic syndrome (MDS). Acute myeloid leukemia patients for whom PTK/ZK monotherapy was ineffective could receive PTK/ZK combined with standard induction chemotherapy. Sixty-three patients received PTK/ZK at doses of 500-1000 mg orally b.i.d. Safety and pharmacokinetic data were collected. Responses were evaluated according to standard bone marrow and peripheral blood criteria. At 1000 mg b.i.d., dose-limiting toxicities of lethargy, hypertension, nausea, emesis and anorexia were observed. Other adverse events related to PTK/ZK were dizziness, weakness, fatigue, diarrhea and pruritus; these were generally mild and reversible. Pharmacokinetic data showed that steady state was reached by day 14, there was no accumulation with repeat dosing and there was no significant increase in exposure at steady state beyond the maximum tolerated dose (MTD). Complete remission was observed in five of 17 AML patients treated with PTK/ZK combined with chemotherapy. In conclusion, the MTD of PTK/ZK is 750 mg orally b.i.d. The drug is generally well tolerated and can be given in combination with chemotherapy for patients with MDS and AML.
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PMID:Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome. 1661 23

Alternative genetic pathways were previously outlined in the pathogenesis of therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML) based on cytogenetic characteristics. Some of the chromosome aberrations, the recurrent balanced translocations or inversions, directly result in chimeric rearrangement of genes for hematopoietic transcription factors (class II mutations) which disturb cellular differentiation. Other genetic abnormalities in t-MDS and t-AML comprise activating point mutations or internal tandem duplications of genes involved in signal transduction as tyrosine kinase receptors or genes more downstream in the RAS-BRAF pathway (class I mutations). The alternative genetic pathways of t-MDS and t-AML can now be further characterized by a different clustering of six individual class I mutations and mutations of AML1 and p53 in the various pathways. In addition, there is a significant association between class I and class II mutations possibly indicating cooperation in leukemogenesis, and between mutations of AML1 and RAS related to subsequent progression from t-MDS to t-AML. Therapy-related and de novo myelodysplasia and acute myeloid leukemia seem to share genetic pathways, and surprisingly gene mutations were in general not more frequent in patients with t-MDS or t-AML as compared to similar cases of de novo MDS and AML studied previously.
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PMID:Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia. 1699 Jul 78

The CellKey (MDS Sciex, South San Francisco, CA) system enables comprehensive pharmacological evaluation of cell surface receptors, including G-protein coupled receptors (GPCRs) and tyrosine kinase receptors, using adherent and suspension cell lines and primary cells. A unique application enabled by the ability of the CellKey system to reliably quantify activation of endogenous receptors is receptor panning. This application allows investigators to easily screen disease-relevant cell types for functionally active target receptors by treating cells with a panel of receptor-specific ligands. Receptor panning of multiple cell types including Chinese hamster ovary, human embryonic kidney 293, HeLa, U-937, U-2 OS, and TE671 cells resulted in the identification of many functionally active, differently coupled endogenous GPCRs, some of which have not been previously documented in the literature. Upon detecting GPCR activation in live cells, unique cellular dielectric spectroscopy (CDS) response profiles are generated within minutes that reflect the signaling pathways utilized and have been shown to be characteristic of Gs, Gq, and Gi GPCRs. The fact that the CDS response profiles are predictive of the G-protein coupling mechanism of the receptor was demonstrated by using examples of subtype-selective agonists/antagonists to identify the subtypes of the endogenous histamine and beta-adrenergic receptors expressed in U-2 OS cells. A direct correlation is shown between receptor subtype G-protein coupling and CDS response profile. In addition, complex pharmacology, including detection of partial agonism and Schild analysis for endogenous receptors, is presented. The CellKey system allows investigators to conduct studies using endogenously expressed receptors to generate data that are physiologically relevant and in disease context.
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PMID:Cellular dielectric spectroscopy: a label-free comprehensive platform for functional evaluation of endogenous receptors. 1711 31

JAK2V617F, a somatic gain-of-function mutation involving the JAK2 tyrosine kinase gene, occurs in nearly all patients with polycythemia vera (PV) but also in a variable proportion of patients with other myeloid disorders; mutational frequency is estimated at approximately 50% in both essential thrombocythemia (ET) and myelofibrosis (MF), up to 20% in certain subcategories of atypical myeloproliferative disorder (atypical MPD), less than 3% in de novo myelodysplastic syndrome (MDS) or acute myeloid leukemia, and 0% in chronic myeloid leukemia (CML). Accordingly, there is now molecular justification for grouping PV, ET, and MF together in a distinct MPD category (i.e., classic, BCR-ABL(-) MPD) that is separate from chronic myeloid leukemia (CML), MDS, and atypical MPD. To date, JAK2V617F has not been described in patients with reactive myeloproliferation, lymphoid disorders, or solid tumor. Therefore, the presence of JAK2V617F strongly suggests an underlying MPD and it is therefore reasonable to consider JAK2V617F-based laboratory tests for the evaluation of polycythemia, primary thrombocytosis, unexplained leukocytosis, bone marrow fibrosis, or abdominal vein thrombosis. Current information on disease-specific prognostic relevance of JAK2V617F is inconclusive and confounded by inter-study differences in the performance of mutation screening assays. Regardless, the discovery of JAK2V617F has reinforced the pathogenetic contribution of JAK-STAT signaling in MPD and identifies JAK2 as a valid drug target.
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PMID:Classification, diagnosis and management of myeloproliferative disorders in the JAK2V617F era. 1712 67

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal bone marrow disorders characterized by both bone marrow failure and a propensity for development of acute myeloid leukemia. The incidence of these conditions has risen sharply over the past several years, making them the most common malignant bone marrow disorders. While the majority of patients are diagnosed with low-grade disease, approximately two-thirds will succumb to complications of peripheral blood cytopenias or progression to acute leukemia. In recent years, there has been striking progress in our understanding of the pathogenesis of these disorders. For example, the recognition of the roles of angiogenesis and cytokine abnormalities in the development of these diseases led to clinical trials with agents such as thalidomide, which yielded encouraging erythroid responses. Subsequent work with the thalidomide derivative lenalidomide resulted in marked erythroid and cytogenetic responses in individuals with the 5q- abnormality. Additionally, the identification of hypermethylation as an important aspect in the pathogenesis of these and other hematological diseases led to clinical trials utilizing the demethylating agents azacitidine and decitibine. These agents are now known to result in trilineage responses in 30% to 50% of patients with MDS with as many as 20% achieving partial or complete remissions. These results have altered the natural history of these diseases in a significant number of patients. Investigators anticipate that further studies with tyrosine kinase, histone deacetylase, and farnesyl transferase inhibitors will contribute to already promising attempts to reverse or block the pathogenesis of these diseases. Other novel agents are being evaluated as investigators continue to make progress for patients affected by these disorders.
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PMID:Recent advances in myelodysplastic syndromes. 1737 99

Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Like most other bone marrow failure syndromes, it is associated with a marked propensity to transform into a myelodysplastic syndrome (MDS) or acute leukemia, with a cumulative rate of transformation to MDS/leukemia that exceeds 20%. The genetic (and/or epigenetic) changes that contribute to malignant transformation in SCN are largely unknown. In this study, we performed mutational profiling of 14 genes previously implicated in leukemogenesis using 14 MDS/leukemia samples from patients with SCN. We used high-throughput exon-based resequencing of whole-genome-amplified genomic DNA with a semiautomated method to detect mutations. The sensitivity and specificity of the sequencing pipeline was validated by determining the frequency of mutations in these 14 genes using 188 de novo AML samples. As expected, mutations of tyrosine kinase genes (FLT3, KIT, and JAK2) were common in de novo AML, with a cumulative frequency of 30%. In contrast, no mutations in these genes were detected in the SCN samples; instead, mutations of CSF3R, encoding the G-CSF receptor, were common. These data support the hypothesis that mutations of CSF3R may provide the "activated tyrosine kinase signal" that is thought to be important for leukemogenesis.
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PMID:Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia. 1749 58

In therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML), at least eight alternative genetic pathways have been defined based on characteristic recurrent chromosome abnormalities. Patients presenting as t-MDS and patients presenting as overt t-AML cluster differently in these pathways. The cytogenetic pattern depends on the type of leukemogenic therapy received: alkylating agents, topoisomerase II inhibitors, or radiotherapy. Three types of gene mutations are observed in MDS and AML: (1) Activating mutations of genes in the tyrosine kinase-RAS/BRAF signal transduction pathway, leading to increased cell proliferation (Class I mutations); (2) Inactivating mutations of genes encoding hematopoietic transcription factors, resulting in disturbed cell differentiation (Class II mutations); and (3) Inactivating mutations of the tumor suppressor gene p53. At least 14 different genes have been identified as mutated in t-MDS and t-AML, clustering differently and characteristically in the eight genetic pathways. Class I and Class II mutations are significantly associated, indicating their cooperation in leukemogenesis The chromosome aberrations and gene mutations detected in the therapy-related and in the de novo subsets of MDS and AML are identical, although the frequencies with which they are observed may differ. Hence, therapy-related and de novo MDS and AML are identical diseases and should be subclassified and treated similarly.
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PMID:Genetic pathways in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia. 1802 56

Myelodysplasia (MDS) and acute myeloid leukemia (AML) are heterogeneous, closely associated diseases arising de novo or following chemotherapy with alkylating agents, topoisomerase II inhibitors, or after radiotherapy. Whereas de novo MDS and AML are almost always subclassified according to cytogenetic characteristics, therapy-related MDS (t-MDS) and therapy-related AML (t-AML) are often considered as separate entities and are not subdivided. Alternative genetic pathways were previously proposed in t-MDS and t-AML based on cytogenetic characteristics. An increasing number of gene mutations are now observed to cluster differently in these pathways with an identical pattern in de novo and in t-MDS and t-AML. An association is observed between activating mutations of genes in the tyrosine kinase RAS-BRAF signal-transduction pathway (Class I mutations) and inactivating mutations of genes encoding hematopoietic transcription factors (Class II mutations). Point mutations of AML1 and RAS seem to cooperate and predispose to progression from t-MDS to t-AML. Recently, critical genetic effects underlying 5q-/-5 and 7q-/-7 have been proposed. Their association and cooperation with point mutations of p53 and AML1, respectively, extend the scenario of cooperating genetic abnormalities in MDS and AML. As de novo and t-MDS and t-AML are biologically identical diseases, they ought to be subclassified and treated similarly.
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PMID:Genetics of therapy-related myelodysplasia and acute myeloid leukemia. 1820 41

Homoharringtonine (HHT), a natural alkaloid extracted from various Cephalotaxus species, exerts its antitumoral and anti-angiogenic activity through an inhibition of protein synthesis and the promotion of apoptosis. ChemGenex Pharmaceuticals Ltd, in collaboration with Stragen Group, is developing omacetaxine mepesuccinate, a semisynthetic formulation of HHT, as a potential treatment for chronic myelocytic leukemia (CML), myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). In preclinical studies, omacetaxine mepesuccinate induced apoptosis in leukemia cell lines. Results from phase II clinical trials revealed omacetaxine mepesuccinate to be active in patients with CML that was resistant to tyrosine kinase inhibitor (TKI) therapy, including those patients who carry the BCR-ABL1T315I mutation, which is highly insensitive to the TKIs imatinib, nilotinib and dasatinib; the therapeutic was also generally well tolerated. Phase II and III clinical trials are underway to assess the activity of omacetaxine mepesuccinate, either alone or in combination with TKIs or other cytotoxic drugs, in patients with CML that is resistant to TKI therapy. Phase I and II clinical trials for omacetaxine mepesuccinate in the treatment of AML and MDS are also ongoing; intravenous, subcutaneous and oral formulations of the drug are being developed. Omacetaxine mepesuccinate appears to hold potential for the treatment of CML and, in particular, imatinib-resistant CML; the development of alternative formulations of the therapeutic further expands the potential for success in drug development.
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PMID:Omacetaxine mepesuccinate--a semisynthetic formulation of the natural antitumoral alkaloid homoharringtonine, for chronic myelocytic leukemia and other myeloid malignancies. 1846 78

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