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)

Neovascularization is increasingly recognized as an important factor in the pathogenesis of hematologic malignancies as well as solid tumors. The complex interactions between several cell types and numerous cytokine mediators suggest the involvement of autocrine and paracrine signaling mechanisms. Vascular endothelial growth factor (VEGF) in particular is critical to both stimulation of leukemic growth and proliferation of endothelial cells. Tyrosine kinase receptors specific for certain growth factors represent attractive target molecules for anticancer therapy. SU5416 is a competitive inhibitor of VEGF receptor subtypes VEGFR-1 and VEGFR-2 and stem cell factor receptor c-kit. Preclinical evidence shows that SU5416 effectively inhibits VEGF-induced endothelial cell proliferation and slows growth of subcutaneous solid tumor xenografts. This agent is in late-stage clinical trials in patients with solid tumors, and a Phase 2 study was recently initiated to evaluate its utility in the treatment of acute myeloid leukemia. In this Phase 2 study, investigators are seeking to determine the response rate to the antiangiogenic agent SU5416. Translational research in this study is intended to aid our understanding of the precise mechanisms by which SU5416 affects acute myeloid leukemia cells and the bone marrow microenvironment.
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PMID:Role of angiogenesis inhibitors in acute myeloid leukemia. 1177 83

Stem cell factor is a haemopoietic growth factor that interacts with the c-kit-encoded transmembrane tyrosine kinase receptor during signal transduction in haemopoietic progenitor stem cells. We have screened 127 Chinese patients with myelodysplastic syndromes or acute myeloid leukaemia for structural rearrangements in the stem cell factor and c-kit genes using Southern blot analysis. No structural rearrangements were detected in any of the bone marrow samples that were tested. It seems that structural rearrangements in the stem cell factor and c-kit genes are rare in Hong Kong patients who have a haematological malignancy.
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PMID:Lack of structural rearrangement in c-kit and stem cell factor genes in Hong Kong Chinese patients with myelodysplastic syndromes or acute myeloid leukaemia. 1183 49

The stem cell factor/c-kit tyrosine kinase receptor pathway has been shown to be important for tumor growth and progression in several cancers, including mast cell diseases, gastrointestinal stromal tumor, acute myeloid leukemia, small cell lung carcinoma, and Ewing sarcoma. Studies using the oral agent STI-571 (Gleevec, Novartis), an inhibitor of the tyrosine kinases bcr-abl, c-kit, and PDGFR, have shown significant responses in patients with chronic myelogenous leukemia and gastrointestinal stromal tumor. With the aim of identifying additional groups of tumors that may use the stem cell factor/c-kit pathway and secondarily may be responsive to STI-571 treatment, this study surveyed 151 primary tumors from patients treated at St. Jude Children's Research Hospital for immunohistochemical expression of c-kit. Formalin-fixed, paraffin-embedded sections were stained with rabbit polyclonal anti-human c-kit (CD117, Dako) using standard avidin-biotin-peroxidase complex technique, antigen retrieval, and an automated stainer. Strong, diffuse staining for c-kit was seen in a proportion of synovial sarcomas, osteosarcomas, and Ewing sarcomas. Strong, diffuse staining was less common in neuroblastomas, Wilms' tumors, and rhabdomyosarcomas and was negative in alveolar soft part sarcomas and desmoplastic small round cell tumors. Tumors with strong, diffuse staining for c-kit in a pattern similar to gastrointestinal stromal tumor may represent suitable targets for new therapeutic agents.
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PMID:C-kit expression in pediatric solid tumors: a comparative immunohistochemical study. 1191 27

Up to 30% of acute myelogenous leukemia (AML) patients harbor an activating internal tandem duplication (ITD) within the juxtamembrane domain of the FLT3 receptor, suggesting that it may be a target for kinase inhibitor therapy. For this purpose we have developed CT53518, a potent antagonist that inhibits FLT3, platelet-derived growth factor receptor (PDGFR), and c-Kit (IC(50) approximately 200 nM), while other tyrosine or serine/threonine kinases were not significantly inhibited. In Ba/F3 cells expressing different FLT3-ITD mutants, CT53518 inhibited IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC(50) of 10-100 nM. In human FLT3-ITD-positive AML cell lines, CT53518 induced apoptosis and inhibited FLT3-ITD phosphorylation, cellular proliferation, and signaling through the MAP kinase and PI3 kinase pathways. Therapeutic efficacy of CT53518 was demonstrated both in a nude mouse model and in a murine bone marrow transplant model of FLT3-ITD-induced disease.
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PMID:CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). 1212 72

Aberrant expression and activating mutations of the class III receptor tyrosine kinase Flt3 (Flk-2, STK-1) have been linked to poor prognosis in acute myeloid leukemia (AML). Inhibitors of Flt3 tyrosine kinase activity are, therefore, of interest as potential therapeutic compounds. We previously described bis(1H-2-indolyl)-1-methanones as a novel class of selective inhibitors for platelet-derived growth factor receptors (PDGFR). Several bis(1H-2-indolyl)-1-methanone derivatives, represented by the compounds D-64406 and D-65476, are also potent inhibitors of Flt3. They inhibit proliferation of TEL-Flt3-transfected BA/F3 cells with IC(50) values of 0.2-0.3 microM in the absence of IL-3 but >10 microM in the presence of IL-3. Ligand-stimulated autophosphorylation of Flt3 in EOL-1 cells and corresponding downstream activation of Akt/PKB are effectively inhibited by bis(1H-2-indolyl)-1-methanones whereas autophosphorylation of c-Kit/SCF receptor or c-Fms/CSF-1 receptor is less sensitive or insensitive, respectively. Flt3 kinase purified by different methods is potently inhibited in vitro, demonstrating a direct mechanism of inhibition. 32D cells, expressing a constitutively active Flt3 variant with internal tandem duplication are greatly sensitized to radiation-induced apoptosis in the presence of D-64406 or D-65476 in the absence but not in the presence of IL-3. Thus, bis(1H-2-indolyl)-1-methanones are potential candidates for the treatment of Flt3-driven leukemias.
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PMID:Bis(1H-2-indolyl)-1-methanones as inhibitors of the hematopoietic tyrosine kinase Flt3. 1214 94

Mutations in signal transduction molecules, which regulate cell differentiation and proliferation, are involved in the development of leukemia. Aberrations of receptor type tyrosine kinases are known to arise from FLT3 mutations in acute myeloid leukemia (AML) and myelodysplastic syndrome, and c-Kit mutations in mast cell tumors. BCR/ABL found in chronic myelogenous leukemia (CML) is a hallmark of the constitutively active forms of cytoplasmic tyrosine kinases. Downstream of the tyrosine kinase is the RAS GTP-binding protein, and genetic mutations related to this protein have been found in a wide variety of malignant tumors including hematopoietic tumors. In the nucleus, transcription factor-encoding genes are frequently detected as the targets of chromosomal translocations found in specific types of leukemias. For instance, the AML1 gene generates AML1/MTG8 chimera by t (8;21) translocation in AML (M2), AML1/EVI-1 chimera by t (3;21) translocation in blastic crisis of CML, and TEL/AML1 chimera in t (12;21) translocation (pre-B cell type acute lymphoblastic leukemia). Another example of abnormal transcription factors is PML/RAR alpha generated by t (15;17) translocation found in acute promyelocytic leukemia. Mutations or deletions of tumor suppressor genes are frequently found in cell cycle regulators such as p53, RB and p16 genes. Therefore, mutations of any molecules involved in the signal transduction pathways from growth factor receptors to inside the nucleus are thought to contribute to neoplastic transformation of hematopoietic cells.
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PMID:[Molecular mechanisms in leukemogenesis]. 1214 88

To date, constitutively activating point mutations reported in hematopoietic growth factor receptors in patients with acute myeloid leukemia (AML) have been restricted to receptors with intrinsic tyrosine kinase activity such as c-kit and FLT3. We describe here a Thr617Asn mutation in the transmembrane domain of the non-tyrosine kinase receptor for granulocyte colony-stimulating factor (G-CSF) in the blast cells of two out of 555 AML patients examined. The mutant receptor conferred growth factor independence on factor-dependent Ba/F3 cells. In the absence of ligand, immunoblotting showed weak phosphorylation of JAK2, STAT3, ERKs 1 and 2 and the receptor itself, and there was approximately 70% of maximal growth in a proliferation assay. All signals were significantly enhanced in the presence of G-CSF. Retroviral transduction of mutant receptor into primary hematopoietic CD34+ cells induced G-CSF independent myeloid differentiation as assessed by the development of neutrophils and surface expression of CD11b and CD14. These results confirm the importance of the transmembrane domain for receptor function and suggest that introduction of an asparagine residue can cause sufficient stabilization of helix-helix interactions in the absence of ligand to activate downstream signaling pathways involved in directing proliferation and differentiation.
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PMID:An activating mutation in the transmembrane domain of the granulocyte colony-stimulating factor receptor in patients with acute myeloid leukemia. 1220 10

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

Imatinib mesylate, a tyrosine kinase inhibitor targeting bcr-abl, platelet-derived growth factor receptor (PDGF-R), and c-Kit, effectively induces hematologic and cytogenetic remissions in bcr-abl(+) chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) with only mild to moderate side effects. Here, we describe the successful treatment of a 64-year-old man with c-Kit(+) secondary acute myeloid leukemia (AML) refractory to standard chemotherapy. Upon 2 weeks of imatinib mesylate administration, the patient achieved a complete hematologic remission in peripheral blood. In addition, complete clearance of leukemic blasts in bone marrow and a significant cytogenetic response lasting for more than 5 months was observed. Sequence analysis of exons 2, 8, 10, 11, and 17 of the c-Kit receptor did not reveal structural alterations as previously described in a subset of AML cases. This is the first report of complete remission achieved upon administration of imatinib mesylate in a patient with highly refractory, secondary AML.
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PMID:Sustained complete hematologic remission after administration of the tyrosine kinase inhibitor imatinib mesylate in a patient with refractory, secondary AML. 1248 Jul 6

Imatinib (Glivec; STI571) is an ATP-competitive kinase inhibitor of c-Abl, BCR/ABL, c-Kit, and platelet-derived growth factor receptor. Overexpression or constitutive activation of Kit by mutations have been associated with various malignancies. Mutations in the intracellular juxtamembrane region of Kit (e.g., V560G) are common in gastrointestinal stromal tumors and have been linked to poor prognosis. Mutations in the kinase domain of Kit (e.g., D816V) have been detected in mastocytosis, acute myeloid leukemia, and germ-cell tumors. To determine the sensitivity of Kit mutants to Imatinib in the same cellular background, wild-type Kit (WTKit), V560GKit and D816VKit were expressed in FDC-P1 cells. Growth of FDC(WTKit) was inhibited by Imatinib with GI50 (a concentration of drug at which 50% inhibition of growth occurs) of 0.1-0.2 microM but FDC(V560GKit) were more sensitive to Imatinib with a GI50 of 0.01-0.025 microM and FDC(D816VKit) were resistant to Imatinib with a GI50 greater than 5 microM. The naturally occurring isoforms of c-Kit did not differ in their sensitivity to Imatinib. Immunoprecipitation and Western blot analysis indicated that 1 microM Imatinib reduced phosphorylation of WTKit and completely blocked phosphorylation of V560GKit but did not affect D816VKit phosphorylation. In signaling studies, addition of stem cell factor (SCF) induced phosphorylation of ERK and Akt by WTKit, and ERK, Akt and STAT3 by V560GKit, which were all blocked by Imatinib. Imatinib also blocked the constitutive activation of Akt and STAT3 by V560GKit but had no affect on the constitutive activation of ERK, Akt, and STAT3 by D816VKit. Overall, these findings demonstrate the increased susceptibility of the Kit juxtamembrane mutant, V560G, and the resistance of the kinase domain mutant, D816V, to Imatinib compared with WTKit.
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PMID:Juxtamembrane mutant V560GKit is more sensitive to Imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant. 2207 14


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