Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide with biologic effects that include regulation of hematopoietic stem cell development, extracellular matrix remodeling, and inflammatory cytokine generation. To delineate the potential role of VEGF in patients with myelodysplastic syndrome (MDS), VEGF protein and receptor expression and its functional significance in MDS bone marrow (BM) were evaluated. In BM clot sections from normal donors, low-intensity cytoplasmic VEGF expression was detected infrequently in isolated myeloid elements. However, monocytoid precursors in chronic myelomonocytic leukemia (CMML) expressed VEGF in an intense cytoplasmic pattern with membranous co-expression of the Flt-1 or KDR receptors, or both. In situ hybridization confirmed the presence of VEGF mRNA in the neoplastic monocytes. In acute myelogenous leukemia (AML) and other MDS subtypes, intense co-expression of VEGF and one or both receptors was detected in myeloblasts and immature myeloid elements, whereas erythroid precursors and lymphoid cells lacked VEGF and receptor expression. Foci of abnormal localized immature myeloid precursors (ALIP) co-expressed VEGF and Flt-1 receptor, suggesting autocrine cytokine interaction. Antibody neutralization of VEGF inhibited colony-forming unit (CFU)-leukemia formation in 9 of 15 CMML and RAEB-t patient specimens, whereas VEGF stimulated leukemia colony formation in 12 patients. Neutralization of VEGF activity suppressed the generation of tumor necrosis factor-alpha and interleukin-1beta from MDS BM-mononuclear cells and BM-stroma and promoted the formation of CFU-GEMM and burst-forming unit-erythroid in methylcellulose cultures. These findings indicate that autocrine production of VEGF may contribute to leukemia progenitor self-renewal and inflammatory cytokine elaboration in CMML and MDS and thus provide a biologic rationale for ALIP and its adverse prognostic relevance in high-risk MDS.
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PMID:Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. 1151 Apr 70

It has been proposed that adoptive immunotherapy, for the treatment of relapsed AML, with cytotoxic T lymphocytes which show a relative specificity for the leukemic cells may have the advantage of maximizing the beneficial anti-leukemic effect whilst minimizing the probability of graft-versus-host disease. In this study we differentiated peripheral blood AML cells in vitro into functional dendritic cells (DCs), as demonstrated by cell morphology, immunophenotype and functional activity, in the presence of GM-CSF, IL-4, TNF-alpha and FLT3 ligand. Such DCs could be differentiated from 77% of AML patients, irrespective of their FAB classification and clinical status and, in all cases tested, the DCs were shown to derive from the leukemic clone by FISH analysis. Importantly, from >60% of AML patients, autologous T lymphocytes stimulated with these in vitro generated leukemic DCs displayed specific cytotoxic activity against AML blasts but low reactivity against autologous non-leukemic targets and HLA-matched normal PBMNCs therefore suggesting that the CTLs were AML-specific. The use of FLT3 ligand in our system resulted in a significantly higher number of leukemic DCs as compared to cultures from which FLT3 ligand was omitted which is obviously advantageous if large numbers of specific CTLs are to be generated in the shortest possible time.
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PMID:Leukemic dendritic cells generated in the presence of FLT3 ligand have the capacity to stimulate an autologous leukemia-specific cytotoxic T cell response from patients with acute myeloid leukemia. 1123 40

Mutations of receptor tyrosine kinases are implicated in the constitutive activation and development of human malignancy. An internal tandem duplication (ITD) of the juxtamembrane (JM) domain-coding sequence of the FLT3 gene (FLT3/ITD) is found in 20% of patients with acute myeloid leukemia (AML) and is strongly associated with leukocytosis and a poor prognosis. On the other hand, mutations of the c-KIT gene, which have been found in mast cell leukemia and AML, are clustered in 2 distinct regions, the JM domain and D816 within the activation loop. This study was designed to analyze the mutation of D835 of FLT3, which corresponds to D816 of c-KIT, in a large series of human hematologic malignancies. Several kinds of missense mutations were found in 30 of the 429 (7.0%) AML cases, 1 of the 29 (3.4%) myelodysplastic syndrome (MDS) cases, and 1 of the 36 (2.8%) acute lymphocytic leukemia patients. The D835Y mutation was most frequently found (22 of the 32 D835 mutations), followed by the D835V (5), and D835H (1), D835E (1), and D835N (1) mutations. Of note is that D835 mutations occurred independently of FLT3/ITD. An analysis in the 201 patients newly diagnosed with AML (excluding M3) revealed that, in contrast to the FLT3/ITD mutation (n = 46), D835 mutations (n = 8) were not significantly related to the leukocytosis, but tended to worsen disease-free survival. All D835-mutant FLT3 were constitutively tyrosine-phosphorylated and transformed 32D cells, suggesting these mutations were constitutively active. These results demonstrate that the FLT3 gene is the target most frequently mutated to become constitutively active in AML.
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PMID:Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. 1129 May 75

Tandem duplication (TD) of the MLL or FLT3 gene in acute myeloid leukemia (AML) has been reported. We examined whether TD of these two genes occurs simultaneously. We analyzed 13 AML and 2 myelodysplastic syndrome patients, including 6 adult patients with trisomy 11 and 9 pediatric patients with TD of the FLT3 gene, using RT-PCR followed by sequencing. Among these, TD of the MLL and FLT3 genes was found in 5 and 10 patients, respectively. Notably, TD of both the MLL and FLT3 genes (coduplication) was detected in two AML patients, who died 6 and 14 months after diagnosis. TD of these two genes in AML is rare; thus, coduplication of these genes in the same patient is predicted to be very rare. Although the mechanisms of TD of both genes are different, development of TD of both genes may be related to an unknown similar etiology in leukemia because the frequency of coduplication of these genes in a single patient is considered to be very low. Further studies of the coduplication of these genes in AML patients may lead to the clarification of its mechanism and clinical implications.
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PMID:Coduplication of the MLL and FLT3 genes in patients with acute myeloid leukemia. 1131 6

Elucidation of the molecular genetic basis of leukaemias has relied on the cloning and characterization of recurring chromosomal translocations. A common theme in acute myeloid leukaemia (AML) associated with balanced reciprocal translocations is the involvement of transcription factors as one or both of the fusion partners. Transcription factors commonly involved in chromosomal translocations include core binding factor (CBF), retinoic acid receptor alpha (RARalpha), ETS family of transcription factors and homeobox gene (HOX) family members. In addition, the recruitment of transcriptional co-activators and co-repressors by these transcription factors suggests that these proteins also may play a critical role in leukaemogenesis. In support of this hypothesis' at least three fusions associated with leukaemias and involving transcriptional co-activators CBP and p300 have been recently cloned. However expression of transcription factor fusion proteins is not sufficient to induce a leukaemic phenotype, as evidenced in part by the long latencies required for disease development in the murine models of the disease. An emerging paradigm is the co-operation between constitutively activated tyrosine kinase molecules, such as FLT3, and transcription factor fusions in the pathogenesis of AML. In such a model, the activated tyrosine kinase confers proliferation and/or anti-apoptotic activity to the hematopoietic cells, while the transcription factor fusion impairs normal differentiation pathways with limited effect on cellular proliferation.
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PMID:Molecular genetics of acute myeloid leukaemia. 1135 23

The prevalence and significance of genetic abnormalities in older patients with acute myeloid leukemia (AML) are unknown. Polymerase chain reactions and single-stranded conformational polymorphism analyses were used to examine 140 elderly AML patients enrolled in the Southwest Oncology Group study 9031 for FLT3, RAS, and TP53 mutations, which were found in 34%, 19%, and 9% of patients, respectively. All but one of the FLT3 (46 of 47) mutations were internal tandem duplications (ITDs) within exons 11 and 12. In the remaining case, a novel internal tandem triplication was found in exon 11. FLT3 ITDs were associated with higher white blood cell counts, higher peripheral blast percentages, normal cytogenetics, and less disease resistance. All RAS mutations (28 of 28) were missense point mutations in codons 12, 13, or 61. RAS mutations were associated with lower peripheral blast and bone marrow blast percentages. Only 2 of 47 patients with FLT3 ITDs also had a RAS mutation, indicating a significant negative association between FLT3 and RAS mutations (P =.0013). Most TP53 mutations (11 of 12) were missense point mutations in exons 5 to 8 and were associated with abnormal cytogenetics, especially abnormalities in both chromosomes 5 and 7. FLT3 and RAS mutations were not associated with inferior clinical outcomes, but TP53 mutations were associated with a worse overall survival (median 1 versus 8 months, P =.0007). These results indicate that mutations in FLT3, RAS, or TP53 are common in older patients with AML and are associated with specific AML phenotypes as defined by laboratory values, cytogenetics, and clinical outcomes. (Blood. 2001;97:3589-3595)
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PMID:FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. 1136 55

Mutations causing constitutive activation of KIT have been shown to be causative in some forms of mastocytosis, and several types of mutations have been associated with myeloproliferative disorders (MPDs), acute myelogenous leukemia (AML), sinonasal lymphomas, and gastrointestinal stromal tumors (GIST). We divide these activating mutation into two types - 'regulatory type' mutations, which affect regulation of the kinase molecule, and 'enzymatic pocket type' mutations, which alter the amino acid sequence directly forming the enzymatic site. KIT inhibitors have been suggested as therapeutic drugs for these conditions, but different types of activating mutations respond differentially to KIT inhibitors, so classification of individuals on the basis of specific mutations is necessary to guide therapy.
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PMID:Classes of c-KIT activating mutations: proposed mechanisms of action and implications for disease classification and therapy. 1137 82

A patient is described with myelodysplastic syndrome (MDS) progressing to acute myeloid leukemia (AML) FAB M4. Cytogenetic analysis revealed an unusual rearrangement between chromosomes 9 and 17, leading to a dicentric chromosome with an insertion of material of unknown origin between both chromosomes. By fluorescence in situ hybridization (FISH), the insertion was shown to be an amplification of part of 17q, involving ERBB2, RARA, and TOP2A genes. The median copy number of ERBB2, RARA, and TOP2A genes in the tumor cells was six (range: 4--10). Only one copy of the MPO gene at 17q21.3 was detected, suggesting a deletion of the telomeric part of 17q. To our knowledge, this is the first report of a 17q amplification in AML.
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PMID:Amplification of ERBB2, RARA, and TOP2A genes in a myelodysplastic syndrome transforming to acute myeloid leukemia. 1142 59

Genomic DNA from 97 cases of adult de novo acute myeloid leukaemia (AML) was screened using polymerase chain reaction (PCR) and conformation-sensitive gel electrophoresis (CSGE) for FLT3 exon 20 mutations. Initial sequencing of four cases, representing the spectrum of CSGE abnormalities, revealed changes affecting codon Asp835 in three cases and also an intron 20 A to G change. In order to identify all possible Asp835 alterations, as well as the frequency of the intronic change nucleotide 2541 + 57 A-->G, the patient PCR products were digested with EcoRV and NlaIII respectively. Seven cases (7.2%) possessed a mutation affecting Asp835; these were identified, following DNA sequencing, as Asp835Tyr (n = 5), Asp835His (n = 1) and Asp835del (n = 1). Alterations affecting Asp835 were not found in 80 normal control DNA samples. In contrast, the nucleotide 2541 + 57 A-->G change was shown to be a polymorphism, with an allelic frequency of 0.24 for the G and 0.76 for the A allele. This study reports, for the first time, point mutations in the human FLT3 gene that, because of their homology with other class III receptor tyrosine kinase mutations, probably result in constitutive activation of the receptor.
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PMID:Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. 1144 93

Vinorelbine (VNR) is a semi-synthetic Vinca rosea alkaloid that has been employed both as a single agent and in combination, and has shown significant antitumor activity. As little is known about VNR activity on human leukemia, we studied its in vitro cytotoxic effect on human leukemia cell lines (FLG 29.1, HL60, K562, Balm 4, CEM and Daudi) and on fresh leukemia cells from 28 patients: 2 acute myeloid leukemia (AML); 3 chronic myeloid leukemia in blastic phase (CML-BP); 5 acute lymphoblastic leukemia (ALL); 18 B-chronic lymphatic leukemia (B-CLL), employing the colorimetric INT assay and determining the IC50. We observed that VNR exerts its cytotoxic activity on leukemic cell lines in a dose-dependent fashion. The lymphoid cell lines appear more sensitive than the myeloid ones to the VNR-dependent growth inhibition. A similar pattern was noticed for leukemia cells in primary cultures. VNR is not effective on CML-BP cells, shows variable activity on the AML and ALL cells and is very effective against B-CLL cells. VNR inhibited the growth of fresh B-CLL cells from 15 of 18 patients, the IC50 doses ranging from 4 ng/ml to 83 microg/ml (doses coinciding with the plasma levels obtained in clinics). These observations strongly suggest that VNR could be useful in clinics for the treatment of B-CLL.
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PMID:In vitro activity of vinorelbine on human leukemia cells. 1145 Aug 90


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