Gene/Protein Disease Symptom Drug Enzyme Compound
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 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute myeloid leukemia with normal karyotype (NK-AML) represents a cytogenetic grouping with intermediate prognosis but substantial molecular and clinical heterogeneity. Within this subgroup, presence of FLT3 (FMS-like tyrosine kinase 3) internal tandem duplication (ITD) mutation predicts less favorable outcome. The goal of our study was to discover gene-expression patterns correlated with FLT3-ITD mutation and to evaluate the utility of a FLT3 signature for prognostication. DNA microarrays were used to profile gene expression in a training set of 65 NK-AML cases, and supervised analysis, using the Prediction Analysis of Microarrays method, was applied to build a gene expression-based predictor of FLT3-ITD mutation status. The optimal predictor, composed of 20 genes, was then evaluated by classifying expression profiles from an independent test set of 72 NK-AML cases. The predictor exhibited modest performance (73% sensitivity; 85% specificity) in classifying FLT3-ITD status. Remarkably, however, the signature outperformed FLT3-ITD mutation status in predicting clinical outcome. The signature may better define clinically relevant FLT3 signaling and/or alternative changes that phenocopy FLT3-ITD, whereas the signature genes provide a starting point to dissect these pathways. Our findings support the potential clinical utility of a gene expression-based measure of FLT3 pathway activation in AML.
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PMID:An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML. 1830 32

Ki11502 is a novel multitargeted receptor tyrosine kinase (RTK) inhibitor with selectivity against platelet-derived growth factor receptor alpha/beta (PDGFRalpha/beta). Ki11502 (0.1-1 nM, 2 days) profoundly caused growth arrest, G(0)/G(1) cell-cycle arrest, and apoptosis associated with down-regulation of Bcl-2 family proteins in the eosinophilic leukemia EOL-1 cells having the activated FIP1-like 1/PDGFRalpha fusion gene. Ki11502 decreased levels of p-PDGFRalpha and its downstream signals, including p-Akt, p-ERK, and p-STAT5, in EOL-1 cells. Of note, Ki11502 was also active against imatinib-resistant PDGFRalphaT674I mutant. In addition, Ki11502 inhibited proliferation of biphenotipic leukemia MV4-11 and acute myelogenous leukemia MOLM13 and freshly isolated leukemia cells having activating mutations in FMS-like tyrosine kinase 3 (FLT3). This occurred in parallel with the drug inhibiting FLT3 and its downstream signal pathways, as measured by fluorescence-activated cell sorting using the phospho-specific antibodies. In addition, Ki11502 totally inhibited proliferation of EOL-1 cells growing as tumor xenografts in SCID mice without any noticeable adverse effects. Taken together, Ki11502 has profound antiproliferative effects on select subsets of leukemia including those possessing imatinib-resistant mutation.
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PMID:Ki11502, a novel multitargeted receptor tyrosine kinase inhibitor, induces growth arrest and apoptosis of human leukemia cells in vitro and in vivo. 1830 36

The development of distinct dendritic cell (DC) subsets is regulated by cytokines. The ligand for the FMS-like tyrosine kinase 3 receptor (Flt3L) is necessary for plasmacytoid DC (pDC) and conventional DC (cDC) maturation. The cytokine GM-CSF inhibits Flt3L-driven pDC production while promoting cDC growth. We show that GM-CSF selectively utilized its signal transducer STAT5 to block Flt3L-dependent pDC development from the lineage-negative, Flt3+ (lin- Flt3+) bone-marrow subset. The signaling molecule STAT3, by contrast, was necessary for expansion of DC progenitors but not pDC maturation. In vivo, STAT5 suppressed pDC formation during repopulation of the DC compartment after bone-marrow ablation. GM-CSF-dependent STAT5 signaling rapidly extinguished pDC-related gene expression in lin- Flt3+ progenitors. Inspection of the Irf8 promoter revealed that STAT5 was recruited during GM-CSF-mediated suppression, indicating that STAT5 directly inhibited transcription of this critical pDC gene. Our results therefore show that GM-CSF controls the production of pDCs by employing STAT5 to suppress IRF8 and the pDC transcriptional network in lin- Flt3+ progenitors.
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PMID:The signal transducer STAT5 inhibits plasmacytoid dendritic cell development by suppressing transcription factor IRF8. 1840 Jan 92

While acute myeloid leukemia (AML) is significantly less common than acute lymphoblastic leukemia (ALL) in childhood, it is significantly more deadly with only half as many children likely to be cured with standard therapy. In addition, the typical treatment for AML is among the most toxic of treatments for pediatric cancer; it includes intensive multiagent chemotherapy and, often, hematopoietic stem cell transplantation. Given the poor prognosis of pediatric AML and the significant toxicity of standard AML therapy, novel therapies are needed. Improved understanding of the molecular and cellular biology of leukemia has facilitated the development of molecularly targeted therapies. In this article, we review progress to date with agents that are showing promise in the treatment of pediatric AML including targeted immunoconjugates, inhibitors of signaling molecules (e.g. FMS-like tyrosine kinase 3 [FLT3], farnesyltransferase, and mammalian target of rapamycin [mTOR]), agents that target epigenetic regulation of gene expression (DNA methyltransferase inhibitors and histone deacetylase inhibitors), and proteasome inhibitors. For the specific agents in each of these classes, we summarize the published preclinical data and the clinical trials that have been completed, are in progress, or are being planned for children with AML. Finally, we discuss potential challenges to the success of molecularly targeted therapy including demonstrating adequate targeting of leukemia stem cells, developing synergistic and tolerable combinations of agents, and designing adequately powered clinical trials to test efficacy in molecularly defined subsets of patients.
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PMID:Molecularly targeted therapies for pediatric acute myeloid leukemia: progress to date. 1834 18

Activating mutations of the FMS-like tyrosine kinase 3 gene (FLT3) occur in approximately one-third of patients with acute myeloid leukaemia (AML) and predict for a poor outcome. Heat shock protein 90 (Hsp90) is a molecular chaperone that is frequently used by cancer cells to stabilise mutant oncoproteins. Mutant FLT3 is chaperoned by Hsp90 in primary AML blasts whereas unmutated FLT3 is not, making Hsp90 inhibitors potentially useful therapeutically. The present study showed that inhibition of Hsp90 by 17-allylamino-17-demethoxygeldanamycin (17-AAG) was cytotoxic to primary AML cells expressing mutant FLT3. Inhibition of Hsp90 results in altered downstream signalling effects in primary AML cells with disruption of Janus kinase-signal transducer and activator of transcription (JAK-STAT), mitogen-activated protein kinase and phosphatidylinositol 3/AKT signalling pathways. Co-treatment of blasts with 17-AAG and cytarabine resulted in a synergistic or additive effect in approximately 50% of AML cases tested. Our results confirm that Hsp90 is a valid molecular target in the therapy of AML. Inhibition of Hsp90 in parallel with conventional AML therapies may have particular benefit in those patients with the poor prognostic FLT3 mutant disease.
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PMID:Heat shock protein 90 inhibition is cytotoxic to primary AML cells expressing mutant FLT3 and results in altered downstream signalling. 1837 9

This study explored the effect of MS-275, a novel histone deacetylase inhibitor (HDACI), against a variety of human leukemia cells with defined genetic alterations. MS-275 profoundly induced growth arrest of acute myelogenous leukemia (AML) MOLM13 and biphenotypic leukemia MV4-11 cells, which possess internal tandem duplication mutation in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD), with IC50s less than 1 microM, as measured by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay on day two of culture. Exposure of these cells to MS-275 decreased levels of total, as well as, phosphorylated forms of FLT3, resulting in inactivation of its downstream signal pathways, including Akt, ERK, and STAT5. Further studies found that MS-275 induced acetylation of heat shock protein 90 (HSP90) in conjunction with ubiquitination of FLT3, leading to degradation of FLT3 proteins in these cells. This was blunted by treatment with the proteasome inhibitor bortezomib, confirming that FLT was degraded via ubiquitin/proteasome pathway. Moreover, we found that further inhibition of MEK/ERK signaling potentiated the action of MS-275 in leukemia cells. Taken together, MS-275 may be useful for treatment of individuals with leukemia possessing activating mutation of FLT3 gene.
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PMID:MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells. 1839 2

FMS-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase that is expressed on the surface of hematopoietic stem cells and plays an important role in normal hematopoiesis. FLT3 is mutated in approximately one-third of cases of acute myeloid leukemia (AML) with normal karyotype. The mutations are most commonly internal tandem duplications found in the juxtamembrane domain of the FLT3 receptor. There are also cases of point mutations within the tyrosine kinase domain. The presence of a FLT3 mutation confers a poorer prognosis in disease-free survival and overall survival. Patients with an FLT3 mutation have poorer outcomes even with a concomitant nucleophosmin1 (NMP1) mutation, which is normally a good prognostic factor. These observations raise the question about how best to treat patients with AML who have FLT3 mutations. There are some retrospective data that allogeneic stem cell transplantation should be offered to patients with FLT3 mutations who have achieved a first remission, but prospective trials are lacking. There are a number of FLT3 inhibitors that are in various stages of clinical testing. It is hoped that this new class of drugs will be combined with traditional cytotoxic therapies to treat AML and improve outcomes in this difficult-to-treat patient population.
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PMID:Implications of FLT3 mutations in the therapy of acute myeloid leukemia. 1847 98

We compared the antitumor activities of the multitargeted tyrosine kinase inhibitors imatinib, sorafenib, and sunitinib to determine which inhibitor is best suited to be used for the treatment of acute myelogenous leukemia (AML). In nine human AML cell lines, sorafenib and sunitinib were more potent inhibitors of cellular proliferation than imatinib (IC50, 0.27 to >40, 0.002-9.1, and 0.007-13 micromol/L for imatinib, sorafenib, and sunitinib, respectively). Sorafenib and sunitinib were potent inhibitors of cells with fms-like tyrosine kinase 3 internal tandem duplication (IC50, 2 and 7 nmol/L) and c-KIT N822K mutations (IC50, 23 and 40 nmol/L). In four cell lines (MV4-11, Kasumi-1, KG-1, and U937) that spanned a range of drug sensitivities, sorafenib and sunitinib had similar activity in apoptosis and cell cycle assays, except that sunitinib did not promote apoptosis in U937 cells. Both drugs inhibited mitogen-activated protein kinase signaling but had no effect on AKT signaling in most of the cell lines tested. Sorafenib was substantially more bound than sunitinib in human plasma (unbound fraction, 0.59% versus 8.4%) and cell culture medium (unbound fraction, 1.3% versus 39%), indicating that sorafenib was more potent than sunitinib and that unbound sorafenib concentrations with activity against most AML cell lines are achievable in vivo. There was more intracellular accumulation of sorafenib than of sunitinib and imatinib in AML cells. Between 1 and 10 micromol/L, sorafenib inhibited the proliferation of six of nine primary AML blast samples by > or =50%. Our results highlight the pharmacologic features of sorafenib that may provide it an advantage in the treatment of AML.
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PMID:Comparison of antitumor effects of multitargeted tyrosine kinase inhibitors in acute myelogenous leukemia. 1848

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis and risk for evolving to acute leukemia. Some molecular abnormalities related to acute myeloid leukemia (AML) transformation have been reported, such as FLT3 (FMS-like tyrosine kinase 3) mutations. FLT3, a member of the class 3 receptor tyrosine kinase family, mediates stem cell proliferation and differentiation, and its mutations, internal tandem duplication (ITD) and Asp835, have been reported in rare MDS patients. We studied FLT3 ITD, prospectively, in 50 MDS patients at diagnosis, at 6 and 12 months follow-up, and at any other time-point if AML transformation was detected. FLT3 ITD was not observed at diagnosis, but during follow-up the mutation was present in 2 of 50 patients (4%). Of these, one case exhibited FLT3 ITD at the end of the 6 months of follow-up in approximately 8% of bone marrow cells; this case evolved into AML at 8 months, at which time FLT3 ITD was present in approximately 85% of bone marrow cells. The other case exhibited FLT3 ITD in 68% of bone marrow cells at 7 months, precisely at the time of AML transformation. Although rare in MDS, FLT3 ITD is associated with a high probability of evolution to AML.
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PMID:FLT3 internal tandem duplication during myelodysplastic syndrome follow-up: a marker of transformation to acute myeloid leukemia. 1850 25

Immunotherapy is now considered in acute myelogenous leukemia (AML). A dendritic cell (DC) phenotype can be induced in primary human AML cells by in vitro culture in the presence of various cytokine combinations. The aim was to investigate whether this phenotypic alteration is associated with altered chemokine release. AML cells were cultured according to four protocols that have been characterized in detail for AML-DC induction: (1) granulocyte-macrophage colony-stimulating factor (GM-CSF) + interleukin-4 (IL-4) days 1-14 and tumor necrosis factor-alpha (TNF-alpha) for days 6-14, (2) GM-CSF + IL-4 + TNF-alpha + FMS-like tyrosine kinase 3-ligand (Fl3-L) for 8 days, (3) GM-CSF + IL-4 + TNF-alpha + Flt3-L + stem cell factor (SCF) + transforming growth factor-beta1 (TGF-beta1) for 8 days, and (4) 25 Gy gamma-irradiation combined with culture in the presence of GM-CSF + SCF + IL-3 for 4 days. Significantly increased AML-DC release of CCL17 and CCL22 was observed for protocols 1, 2, and 3, whereas effects on CCL2-5, CXCL8, and CXCL10 differed in all protocols. Neutralization studies using a transwell migration assay demonstrated the increased level of CCL17 and CCL22 release was important for AML-DC chemotaxis of normal T cells. Induction of a dendritic AML cell phenotype is associated with an altered chemokine release profile. Detailed characterization of chemokine release should be included in future studies of AML-DC vaccination.
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PMID:In vitro induction of a dendritic cell phenotype in primary human acute myelogenous leukemia (AML) blasts alters the chemokine release profile and increases the levels of T cell chemotactic CCL17 and CCL22. 1854 60


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