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

Although mast cells (MC) appear to be myeloid cells, MC lineage involvement in myelogenous malignancies has been described only rarely. Based on clonal evolution, biology of afflicted cells, and disease criteria, three major groups of patients have been recognized: The first meets criteria for both diagnoses 'systemic mastocytosis' and 'associated hematologic clonal non-mast cell lineage disease (AHNMD)'. In such patients, myeloproliferative (MPS) or myelodysplastic syndromes (MDS), or acute myeloid leukemia (AML) is diagnosed apart from mastocytosis. In a second group of patients, large numbers of very immature MC-lineage cells (metachromatically granulated blast-like cells) are detectable, but the criteria to diagnose mastocytosis are not met. These patients have advanced myeloid neoplasms (MDS or MPS with blast cell increase, or AML) and variably suffer from mediator-related symptoms (flush, GI-tract ulcer, diarrhoea, coagulopathy). In some cases, the disease mimics mast cell- or basophilic leukemia. In contrast to basophilic leukemia, however, the metachromatic cells are strongly KIT+ and tryptase+. In contrast to true mast cell leukemia (MCL), MC do not form multifocal dense infiltrates in the bone marrow. Also, MC lack CD2 and CD25, and the C-KIT mutation Asp-816-Val. We propose the term 'myelomastocytic leukemia' or 'myelodysplastic mast cell syndrome' for these cases. In a third group of patients, myeloid neoplasms (MDS, MPS, AML) show constitutive expression of MC-associated antigens (tryptase, histamine) or mastocytosis-related gene defects (mutated C-KIT) without significant increase in metachromatic cells or criteria of mastocytosis. Whether these neoplasms display aberrant gene expression (or gene defects) or represent 'pre-pre-mast cell leukemias', remains unknown.
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PMID:Myelomastocytic overlap syndromes: biology, criteria, and relationship to mastocytosis. 1137 85

An improved understanding of how leukemia cells grow and become resistant to treatment remains critical for developing more effective therapies. We have identified activating mutations of c-kit at codon 816 (Asp(816) ) from a revertant of the cytokine-dependent acute myeloid leukemia (AML) cell line, MO7e (D816H), and de novo childhood AML (D816N). Following transduction of the mutant c-kit cDNAs, MO7e cells acquire a growth advantage and resistance to apoptosis in response to chemotherapeutic drugs and ionizing radiation, in addition to cytokine-independent survival. Although stimulation of mutant c-kit-bearing MO7e cells with stem cell factor (SCF), a ligand for c-Kit, does not have a significant effect on cell proliferation, SCF further inhibits apoptosis induced by cytotoxic agents. These results suggest a potentially important role of Asp(816) mutations of c-kit in both malignant cell proliferation and resistance to therapy.
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PMID:Activating mutations of c-kit at codon 816 confer drug resistance in human leukemia cells. 1137 69

Activating mutations of c-kit at codon 816 (Asp(816)) have been identified in variety of malignancies, including acute myeloid leukemia (AML), mastocytosis and germ cell tumors. The mutant c-Kit receptor confers cytokine independence and induces tumorigenicity. However, the molecular mechanisms, particularly the changes in the signal transduction pathways, responsible for these biological effects induced by mutant c-Kit are largely undefined. Using the human embryonic kidney cell line, 293, we show in the current report that constitutive activation of STAT3 and STAT1 is associated with D816H mutant c-Kit. Transfection of dominant negative STAT3, but not STAT1 inhibits mutant c-Kit mediated anchorage-independent growth in vitro and tumor formation in vivo. Expression of constitutively activated STAT3 restores the mutant c-Kit receptor's transforming ability in 293 cells. These results demonstrate that activation of STAT3 by Asp(816) mutant c-Kit is required for the anchorage-independent growth and tumorigenicity induced by Asp(816) mutant c-Kit.
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PMID:STAT3 activation is required for Asp(816) mutant c-Kit induced tumorigenicity. 1149 48

Hereditary mutations associated with hematologic malignancies are rare. Heterozygous mutations affecting the hematopoietic transcription factor CBFA2 (also AML1/RUNX1) were recently reported to be associated with familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML, MIM 601399). A new 3-generation family with FPD/AML with a novel CBFA2 mutation is described. In this family, AML was diagnosed in a second-generation male. After allogeneic stem cell transplantation from his human leukocyte antigen-identical sister, a donor-derived, genetically identical leukemia developed in the recipient and the donor. Sequencing analysis identified a G-to-T transition within the CBFA2 gene, which involves codon 198, encoding a conserved aspartic acid within the DNA- binding Runt domain. Three of 5 siblings affected with the FPD/AML trait harbored the mutation in a heterozygous form. This experience underscores the necessity of performing mutation analysis of the CBFA2 gene before sibling allogeneic transplantation in families with FPD/AML.
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PMID:A novel CBFA2 single-nucleotide mutation in familial platelet disorder with propensity to develop myeloid malignancies. 1167 61

Substitution of valine (Val) for aspartic acid (Asp) at codon 814 constitutively activates murine c-kit receptor tyrosine kinase (KIT), and Asp816Val mutation, corresponding to murine Asp814Val mutation, is found in patients with mastocytosis and acute myelocytic leukemia. However, the signal transduction pathways responsible for oncogenesis by the Asp814Val mutant (KIT(Val814)) are not fully understood. To examine the oncogenic signal transduction of KIT(Val814), we converted 20 tyrosine (Tyr) residues to phenylalanine (Phe) in the cytoplasmic domain of KIT(Val814) or deleted the C-terminal region containing 2 other tyrosine residues (Del). Among various KIT(Val814)- derived mutants, KIT(Val814-Tyr719Phe) and KIT(Val814-Del) severely impaired receptor tyrosine phosphorylation and association with the p85 subunit of phosphatidylinositol 3'-kinase (p85 (PI3-K)). Moreover, KIT(Val814-Tyr719Phe) and KIT(Val814-Del) failed to induce ligand-independent growth in Ba/F3 cells, indicating that Tyr719, the binding site for p85(PI3-K), and the C-terminal region are indispensable for factor-independent growth by KIT(Val814). Although the C-terminal region was also required for ligand-dependent growth by wild-type KIT (KIT(WT)), the Tyr719Phe substitution had negligible effects on ligand-dependent growth by KIT(WT). Furthermore, dominant-negative PI3-K significantly inhibited ligand-independent growth by KIT(Val814). These results demonstrate that Tyr719 is crucial for constitutive activation of KIT(Val814), but not for the ligand-induced activation of KIT(WT), and that the downstream signaling of PI3-K plays an important role in ligand-independent growth and tumorigenicity by KIT(Val814), thereby suggesting that KIT(Val814) is a unique activating mutation that leads to a distinguishable function from the effects of KIT(WT).
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PMID:Necessity of tyrosine 719 and phosphatidylinositol 3'-kinase-mediated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the Asp814Val mutation. 1239 43

FLT3 is a receptor tyrosine kinase that is expressed on early hematopoietic progenitor cells and plays an important role in stem cell survival and differentiation. Two different types of functionally important FLT3 mutations have been identified. Internal tandem duplication mutations arise from duplications of the juxtamembrane portion of the gene and result in constitutive activation of the FLT3 protein. This alteration has been identified in approximately 20% to 30% of patients with acute myelogenous leukemia and appears to be associated with a worse prognosis. The second type of FLT3 mutation, missense mutations at aspartic acid residue 835, occurs in approximately 7.0% of acute myelogenous leukemia cases. These mutations also appear to be activating and to portend a worse prognosis. Identification of FLT3 mutations is important because it provides prognostic information and may play a pivotal role in determining appropriate treatment options. We have developed an assay to identify both internal tandem duplication and D835 FLT3 mutations in a single multiplex polymerase chain reaction. After amplification, the polymerase chain reaction products are analyzed by capillary electrophoresis for length mutations and resistance to EcoRV digestion. Here we describe the performance characteristics of the assay, assay validation, and our clinical experience using this assay to analyze 147 clinical specimens.
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PMID:Detection of FLT3 internal tandem duplication and D835 mutations by a multiplex polymerase chain reaction and capillary electrophoresis assay. 1270 74

Myeloid sarcoma is an extramedullary tumour that typically occurs in the setting of acute myeloid leukaemia (AML), or myeloproliferative disorders. In AML, two types of mutations in Fms-like tyrosine kinase 3 (FLT3) have been described; internal tandem duplications (ITD) and point mutations at aspartic acid residue 835 (D835). We analysed 24 myeloid sarcoma specimens from 20 patients for FLT3 ITD and D835 mutations. FLT3 ITD mutations were identified in three of 20 cases (15%); no D835 mutations were identified. The ITD inserts ranged in size from 33 to 198 base pairs (bp) and represented approximately 20-40% of the FLT3 alleles. Two cases showed discordance in FLT3 ITD mutational status. In one case, the leukaemia specimen was positive for a FLT3 ITD mutation and the myeloid sarcoma specimen was negative. In the second case, the myeloid sarcoma was positive for a FLT3 ITD mutation at diagnosis, but negative in subsequent relapse samples. Our findings suggest that small molecule inhibitors of FLT3 may be useful therapeutic agents for treatment of myeloid sarcomas-containing FLT3 mutations, however, the potential for discordance between the leukaemia and myeloid sarcoma, necessitates that the myeloid sarcoma tumour itself be analysed for FLT3 mutations.
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PMID:FLT3 mutations in myeloid sarcoma. 1535 81

FLT3 mutations have been reported to be the most frequent mutation in acute myeloid leukemia (AML). No data currently exist regarding FLT3 mutations in Southeast Asian patients. In this study, the incidence and type of FLT3 mutation in a large series of Thai AML patients were determined. FLT3 internal tandem duplication (ITD) mutations were observed in 24.6%, FLT3 tyrosine kinase domain mutations in 3.1%, and dual mutations in 2.7% of 256 newly diagnosed Thai AML patients. ITD mutations were mostly restricted to the juxtamembrane domain, and the in-frame ITD length varied from 21 to 201 base pairs. Six types of point mutations were identified, including Asp835Tyr, Asp835His, Asp835Glu, Asp835Ala, Ile836, and a novel mutation, Asp835Del/Ile836Val, which resulted in the loss of aspartic acid and substitution of isoleucine by valine. A rare leukemia karyotype, trisomy 11, was found to coexist with this novel FLT3 mutation, whereas the majority of patients with FLT3 mutations had a normal karyotype. Overall, FLT3 mutation was associated with a significantly higher white blood cell count and older age than the wild-type FLT3. In conclusion, the incidence of FLT3 mutation in Thailand is as high as that of western countries. The clinical significance of the novel mutation requires further studies in a larger population.
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PMID:Mutations of the FLT3 gene in adult acute myeloid leukemia: determination of incidence and identification of a novel mutation in a Thai population. 1621 60

Evidence from clinical and laboratory studies suggests that angiogenesis is important in the progression of solid tumours and hematologic malignancies. We have shown that the naturally occurring tetrapeptide Acetyl-Ser-Asp-Lys-Pro (AcSDKP) is a potent angiogenic factor normally present at nanomolar concentrations in the blood. A murine leukemia model was used to assess whether there was a correlation between levels of endogenous AcSDKP and the development of disease. Levels of AcSDKP in the plasma and bone marrow (BM) cells from mice bearing an acute myeloid leukemia (AML) were five- to ten-fold greater than those in non-leukemic mice. Furthermore, a strong correlation between the concentration of endogenous AcSDKP and the progression of AML was demonstrated. These results are consistent with the marked increase in BM vascularity observed in leukemic mice. The physiologic relevance of these findings awaits further studies and the contribution of AcSDKP to the pathogenesis of leukemia is under investigation.
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PMID:Evidence for an association of high levels of endogenous Acetyl-Ser-Asp-Lys-Pro, a potent mediator of angiogenesis, with acute myeloid leukemia development. 1706 80

Activating mutations in the Kit receptor are frequently observed in various malignancies, pointing Kit as a molecule of interest for drug inhibition. When mutated on Asp 816 (corresponding to Asp 814 in the mouse), as preferentially found in human mastocytosis and acute myeloid leukemia, Kit became non-sensitive to imatinib mesylate (Gleevec). Erythroleukemic cells isolated from Spi-1/PU.1 transgenic mice express Kit mutated at codon 814 (Kit(D814Y) or Kit(D814V)) or codon 818 (Kit(D818Y)). Using these cells in vitro, we demonstrate that the tyrosine kinase inhibitor SU5416 (Semaxinib) induces growth arrest and apoptosis independent of the mutation type by inhibiting the functions of Kit, including Kit autophosphorylation and activation of Akt, Erk1/Erk2 and Stat3 downstream signaling pathways. These findings indicate that SU5416 may be a promising tool to kill cancer cells driven by Kit oncogenic mutations that are resistant to treatment with imatinib mesylate.
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PMID:Semaxinib (SU5416) as a therapeutic agent targeting oncogenic Kit mutants resistant to imatinib mesylate. 1717 66


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