UMLS:C0023473 - FACTA Search

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Query: UMLS:C0023473 (chronic myeloid leukemia)
18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The novel hematopoietic growth factor FLT3 ligand (FL) is the cognate ligand for the FLT3, tyrosine kinase receptor (R), also referred to as FLK-2 and STK-1. The FLT3R belongs to a family of receptor tyrosine kinases involved in hematopoiesis that also includes KIT, the receptor for SCF (stem cell factor), and FMS. the receptor for M-CSF (macrophage colony- stimulating factor). Restricted FLT3R expression was seen on human and murine hematopoietic progenitor cells. In functional assays recombinant FL stimulated the proliferation and colony formation of human hematopoietic progenitor cells, i.e. CD34+ cord and peripheral blood, bone marrow and fetal liver cells. Synergy was reported for co-stimulation with G-CSF (granulocyte-CSF). GM-CSF (granulocyte-macrophage CSF), M-CSF, interleukin-3 (IL-3), PIXY-321 (an IL-3/GM-CSF fusion protein) and SCF. In the mouse, FL potently enhanced growth of various types of progenitor/precursor cells in synergy with G-CSF, GM-CSF, M-CSF, IL-3, IL-6, IL-7, IL-11, IL-12 and SCF. The well-documented involvement of this ligand-receptor pair in physiological hematopoiesis brought forth the question whether FLT3R and FL might also have a role in the pathobiology of leukemia. At the mRNA level FLT3R was expressed by most (80-100%) cases of AML (acute myeloid leukemia) throughout the different morphological subtypes (MO-M7), of ALL(acute lymphoblastic leukemia) of the immunological subtypes T-ALL and BCP-ALL (B cell precursor ALL including pre-pre B-ALL, cALL and pre B-ALL), of AMLL (acute mixed-lineage leukemia), and of CML (chronic myeloid leukemia) in lymphoid or mixed blast crisis. Analysis of cell surface expression of FLT3R by flow cytometry confirmed these observations for AML (66% positivity when the data from all studies are combined), BCP-ALL (64%) and CML lymphoid blast crisis (86%) whereas less than 30% of T-ALL were FLT3R+. The myeloid, monocytic and pre B cell type categories also contained the highest proportions of FLT3R+ leukemia cell lines . In contrast to the selective expression of the receptor, FL expression was detected in 90-100% of the various cell types of leukemia cell lines from all hematopoietic cell lineages. The potential of FL to induce proliferation of leukemia cells in vitro was also examined in primary and continuously cultured leukemia cells. The data on FL-stimulated leukemia cell growth underline the extensive heterogeneity of primary AML and ALL samples in terms of cytokine-inducible DNA synthesis that has been seen with other effective cytokines. While the majority of T-ALL (0-33% of the cases responded proliferatively; mean 11%) and BCP-ALL (0-30%; mean 20%) failed to proliferate in the presence of FL despite strong expression of surface FLT3R, FL caused a proliferative response in a significantly higher percentage of AML cases (22-90%; mean 53%). In the panel of leukemia cell lines examined only myeloid and monocytic growth factor- dependent cell lines increased their proliferation upon incubation with FL, whereas all growth factor-independent cell lines were refractory to stimulation. Combinations of FL with G-CSF, GM-CSF, M-CSF, IL-3, PIXY- 321 or SCF and FL with IL-3 or IL-7 had synergistic or additive mitogenic effects on primary AML and ALL cells, respectively. The potent stimulation of the myelomonocytic cell lines was further augmented by addition of bFGF (basic fibroblast growth factor), GM-CSF, IL-3 or SCF. The inhibitory effects of TGF-beta 1 (transforming growth factor-beta 1) on FL- supported proliferation were abrogated by bFGF. Taken together, these results demonstrate the expression of functional FLT3R capable of mediating FL- dependent mitogenic signaling in a subset of AML and ALL cases further underline the heterogeneity of AML and ALL samples in their proliferative response to cytokine.
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PMID:Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. 861 33

Myeloproliferative disorders are clonal disorders of the hematopoietic stem cell and comprise a spectrum of more or less well-defined clinical entities: polycythaemia vera, chronic myeloid leukemia, essential thrombocythaemia, and agnogenic myeloid metaplasia. Myelofibrosis, which contributes substantially to the impaired hematopoiesis, is commonly observed in myeloproliferative disorders but it represents the criterion of agnogenic myeloid metaplasia also termed idiopathic myelofibrosis. Although progress has been made in the elucidation of the pathogenesis of myelofibrosis, it still remains unclear. The aim of this review is to address the new insights that outline the potential role of TGF-beta in the promotion of myelofibrosis, through its release from megakaryocytes/platelets, particularly in agnogenic myeloid metaplasia.
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PMID:TGF-beta and megakaryocytes in the pathogenesis of myelofibrosis in myeloproliferative disorders. 875 Jun 21

Genomic instability is one mechanism proposed to play a role in the disease progression of chronic myeloid leukemia (CML). Microsatellite regions in the type II transforming growth factor-beta receptor (TGF-beta RII) gene appear to be targets for mutation in some cancers displaying microsatellite instability (replication error phenotype, RER+). Furthermore, TGF-beta RII mutations in RER+ tumors have been associated with decreased TGF-beta RII mRNA levels. As TGF-beta is a potent negative growth regulator of hematopoietic cells, investigations were undertaken to determine whether inactivation of the receptor by microsatellite alteration might be involved in the progression of CML. Analysis of TGF-beta RII mRNA expression by RNase protection, with comparison of cells from the chronic, accelerated and blast phases of CML, showed no change in TGF-beta RII transcript levels during disease progression. However, during each phase of the disease, low levels of TGF-beta RII were detected when compared with the hematopoietic cells of normal donors. Furthermore, this decreased expression was also observed in the other myeloproliferative disorders, polycythemia rubra vera (PRV) and essential thrombocythemia (ET). The leukemia cell lines K562 and HL-60 had no detectable TGF-beta RII mRNA. Two microsatellite regions found altered in RER+ colon cancers were analyzed to establish if these sequences were aberrant in CML. No alteration was detected in either of these regions in any phase of the disease. These results suggest that alterations of the microsatellite regions in the TGF-beta RII gene are not involved in the progression of CML. Decreased expression of TGF-beta RII in CML cells and leukemia cell lines raises the possibility that altered expression of the receptor may play a role in the initiation and/or maintenance of the disease state.
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PMID:The TGF-beta type II receptor in chronic myeloid leukemia: analysis of microsatellite regions and gene expression. 1021 59

Kermit is a Xenopus orthologue of human GIPC1/GIPC, which interacts with Frizzled-3 (FZD3) class of WNT receptor to modulate WNT signaling. GIPC1 interacts with TGFbeta type III receptor to enhance TGFbeta signaling. We have recently cloned and characterized a novel GIPC1-related gene, GIPC2. During isolation of GIPC2, we identified another novel GIPC1-related gene, GIPC3, by using bioinformatics. In this study, we isolated GIPC3 cDNAs from poly(A)+ RNA of human fetal lung. GIPC3 encoded a 312-amino-acid protein with a central PDZ domain, which showed 59.9% total-amino-acid identity with GIPC1, 55.3% total-amino-acid identity with GIPC2, and 57.2% total-amino-acid identity with Xenopus Kermit. GIPC3 gene on human chromosome 19p13.3 was found to consist of 6 exons, just like GIPC1 gene and GIPC2 gene. The 4.5-kb GIPC3 mRNA was almost ubiquitously expressed in normal adult tissues as well as in normal fetal tissues. Expression level of GIPC3 mRNA was relatively higher in jejunum, followed by lymph node, parietal lobe in brain, fetal spleen, and fetal thymus. GIPC3 mRNA was expressed in cervical cancer cell line HeLa S3, chronic myelogenous leukemia cell line K-562, and melanoma cell line G-361. GIPC3 mRNA was also expressed in gastric cancer cell lines TMK1 and MKN7; however, expression level of GIPC3 mRNA in TMK1 and MKN7 cells were significantly lower than that in normal stomach. This is the first report on molecular cloning of GIPC3, the third member of the GIPC gene family.
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PMID:Molecular cloning and characterization of human GIPC3, a novel gene homologous to human GIPC1 and GIPC2. 1183 71

AML1/Evi-1 is a chimeric protein that is derived from t(3;21), found in blastic transformation of chronic myelogenous leukemia. It is composed of the N-terminal AML1 portion with the DNA-binding Runt domain and the C-terminal Evi-1 portion. It has been shown to dominantly repress AML1-induced transactivation. The mechanism for it has been mainly attributed to competition with AML1 for the DNA-binding and for the interaction with PEBP2beta (CBFbeta), a partner protein which heterodimerizes with AML1. It was recently found that Evi-1 interacts with C-terminal binding protein (CtBP) to repress TGFbeta-induced transactivation. Here, we demonstrate that AML1/Evi-1 interacts with CtBP in SKH1 cells, a leukemic cell line which endogenously overexpresses AML1/Evi-1 and that AML1/Evi-1 requires the interaction with CtBP to repress AML1-induced transactivation. The association with CtBP is also required when AML1/Evi-1 blocks myeloid differentiation of 32Dcl3 cells induced by granulocyte colony-stimulating factor. Taken together, it is suggested that one of the mechanisms for AML1/Evi-1-associated leukemogenesis should be an aberrant recruitment of a corepressor complex by the chimeric protein.
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PMID:The t(3;21) fusion product, AML1/Evi-1 blocks AML1-induced transactivation by recruiting CtBP. 1196 42

Receptor and non-receptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating gastrointestinal cancer. Imatinib mesilate (STI-571, Gleevec(TM)), an inhibitior of bcr-abl TK, which was primarily designed to treat chronic myeloid leukemia is also an inhibitor of c-kit receptor TK, and is currently the drug of choice for the therapy of metastatic gastrointestinal stromal tumors (GISTs), which frequently express constitutively activated forms of the c-kit-receptor. The epidermal growth factor receptor (EGFR), which is involved in cell proliferation, metastasis and angiogenesis, is another important target. The two main classes of EGFR inhibitors are the TK inhibitors and monoclonal antibodies. Gefitinib (ZD1839, Iressa(TM)) has been on trial for esophageal and colorectal cancer (CRC) and erlotinib (OSI-774, Tarceva(TM)) on trial for esophageal, colorectal, hepatocellular, and biliary carcinoma. In addition, erlotinib has been evaluated in a Phase III study for the treatment of pancreatic cancer. Cetuximab (IMC-C225, Erbitux(TM)), a monoclonal EGFR antibody, has been FDA approved for the therapy of irinotecan resistant colorectal cancer and has been tested for pancreatic cancer. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are critical regulators of tumor angiogenesis. Bevacizumab (Avastin(TM)), a monoclonal antibody against VEGF, was efficient in two randomized clinical trials investigating the treatment of metastatic colorectal cancer. It is also currently investigated for the therapy of pancreatic cancer in combination with gemcitabine. Other promising new drugs currently under preclinical and clinical evaluation, are VEGFR2 inhibitor PTK787/ZK 222584, thalidomide, farnesyl transferase inhibitor R115777 (tipifarnib, Zarnestra(TM)), matrix metalloproteinase inhibitors, proteasome inhibitor bortezomib (Velcade(TM)), mammalian target of rapamycin (mTOR) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, platelet derived growth factor receptor (PDGF-R) inhibitors, protein kinase C (PKC) inhibitors, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitors, Rous sarcoma virus transforming oncogene (SRC) kinase inhibitors, histondeacetylase (HDAC) inhibitors, small hypoxia-inducible factor (HIF) inhibitors, aurora kinase inhibitors, hedgehog inhibitors, and TGF-beta signalling inhibitors.
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PMID:Molecularly targeted therapy for gastrointestinal cancer. 1589 18

Chronic myelogenous leukaemia (CML) is a disorder of the haematopoietic stem cell that results in malignant expansion of myeloid cells with a cytogenetic abnormality, and translocation between chromosomes 9 and 22, known as the Philadelphia chromosome. It has been hypothesized that genetic factors other than histocompatibility disparity may play a role in predisposition to developing CML. In this regard, T helper types 1 and 2 (Th1 and Th2) cytokines and their gene polymorphism seem to be important. Overall expression and secretion of cytokines are dependent, at least in part, on genetic polymorphism (nucleotide variations) within the promoter region or other regulatory sequences of cytokine genes. The majority of polymorphisms described are single nucleotide polymorphism (SNPs). The objective of this study was to analyse the genetic profile of Th1 and Th2 cytokines in 30 Iranian patients with CML and 40 healthy subjects. In the patients and control subjects, the allelic and genotype frequencies were determined for the cytokine genes. All typing were performed with a polymerase chain reaction-sequence-specific primers (PCR-SSP) assay. Allele and genotype frequencies were calculated and compared with those of normal controls. The results showed that the most frequent genotypes in our patients were transforming growth factor (TGF)-beta TG/TG, interferon (IFN)-gamma AT, interleukin (IL)-4 CC at position -590, TT at position -33, and IL-10 ACC/ACC and ATA/ATA. In contrast, the genotypes TGF-beta CG/CG, IL-2 TT at position -330, IL-4 CT at position -590, CT at position -33, and IL-10 GCC/ACC were seen at much lower frequencies. The results suggest that production of TGF-beta in CML patients is higher and production of IL-4 and IL-10 is lower than in normal subjects.
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PMID:Cytokine gene polymorphism in Iranian patients with chronic myelogenous leukaemia. 1593 21

Loss of transforming growth factor (TGF)-beta signaling has been implicated in malignant transformation of various tissues. Smad4 plays a central role in the signal transduction of TGF-beta. Deletion or mutation of Smad4 has been described in a number of cancers. This study was aimed to investigate a potential role of Smad4 in leukemia including its expression and location in blast cells. The mononuclear cells were separated from bone marrow of leukemia patients. The samples, blast cells of which were more than 90% in mononuclear cells, were selected. The expression and location of Smad4 protein were analyzed by immunohistochemistry methods. The results showed that the Smad4 protein located mainly in nucleus, part of this protein located in cytoplasma, the expressions of Smad4 were not detected in 6 out of 9 ALL patients, in 7 out of 24 AML patients and in 1 out of 2 CML patients; these leukemia patients, in whose cells the expression of Smad4 was not detected, included one L1 and one L3, four L2, one M0, one M1, two M2a, one M3a, one M4b, one M6 and one CML. In conclusion, the Smad4 protein was mainly in nucleus, the deletion or functional change of Smad4 may related with the pathogenesis of human AML.
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PMID:[Expression of Smad4 in leukemia cells]. 1692 97

p27KIP1 is known as a regulator of cellular differentiation and apoptosis in human cancer cells. We have previously reported that human chronic myeloid leukemia (CML) KU812 and K562 cells show inhibited cellular proliferation in response to treatment with activin A, a member of TGF-beta superfamily. Apoptosis and erythroid differentiation can be induced in KU812 and K562 cells, respectively. We report herein that activin A induced the expression of p27KIP1 in CML cells along with the induction of cellular differentiation and apoptosis. There are putative binding sequences of erythroid-related transcription factor GATA-1 in the promoter region of the human p27KIP1 gene. Expression of GATA-1 protein in activin A-treated KU812 and K562 cells showed dissimilar regulation in these two cell lines. Induction of p27KIP1 was commonly observed, but it did not correspond to the expression levels of GATA-1 in either line of activin A-treated CML cells. In addition, ERK protein was rapidly and transiently activated with activin A in both types of CML cells, suggesting that phosphorylation of ERK is required for activin A signaling in CML cells. These results indicate that both p27KIP1 induction and regulation of GATA-1 play essential roles in activin A-induced erythroid differentiation and apoptosis.
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PMID:p27KIP1 and GATA-1 are potential downstream molecules in activin A-induced differentiation and apoptosis pathways in CML cells. 1701 99

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterized by uncontrolled growth of progenitor cells expressing the tyrosine kinase fusion gene product, Bcr-Abl. At present, little is known regarding how TGFbeta, and downstream Smad transcription factors, influence CML cell proliferation in the context of Bcr-Abl expression. Here we show that ectopic Bcr-Abl expression dramatically increases TGFbeta/Smad-dependent transcriptional activity in Cosl cells, and that this may be due to enhancement of Smad promoter activity. Bcr-Abl expressing TF-1 myeloid cells are more potently growth arrested by TGFbeta compared to the parental TF-1 cell line. Additionally, growth of Bcr-Abl-expressing CD34+ cells from chronic phase CML patients is inhibited by TGFbeta and, interestingly, treatment of a non-proliferating CD34+ CML cell sub-population with the TGFbeta kinase inhibitor SB431542 enhanced cell death mediated by the Bcr-Abl inhibitor imatinib. Our data suggest that the expression of Bcr-Abl leads to hyper-responsiveness of myeloid cells to TGFbeta, and we hypothesise that this novel cross-regulatory mechanism might play an important role in maintaining the transformed progenitor cell population in CML.
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PMID:Upregulation of the TGFbeta signalling pathway by Bcr-Abl: implications for haemopoietic cell growth and chronic myeloid leukaemia. 1734 36

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