Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocyte growth factor (HGF) has been known as a multiple function factor, which also stimulates early haematopoiesis. In this study, we found that HGF was expressed at both the RNA and protein levels in acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML). In patients with AML (n = 20) and CML (n = 5), bone marrow plasma HGF concentrations were 20.44 +/- 6.26 (mean +/- s.e.) ng ml-1 and 7.17 +/- 0.53 ng ml-1 respectively. These were significantly higher (P < 0.01) than the value for normal subjects (n = 26): mean 0.92 +/- 0.09 ng ml-1. Constitutive HGF production was observed in freshly prepared leukaemic blast cells from three patients with high HGF levels of bone marrow plasma. Expression of HGF mRNA was correlated with bone marrow plasma HGF levels. After complete remission was obtained in six patients, bone marrow plasma HGF levels were significantly decreased. In contrast, the HGF mRNA was less abundantly expressed in acute lymphoid leukaemia (ALL). In patients with ALL (n = 5), bone marrow plasma HGF concentration (0.69 +/- 0.14 ng ml-1) remained low within the value for normal subjects. These results suggest that some populations of myeloid lineage cells have the ability to produce HGF.
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PMID:Hepatocyte growth factor levels in bone marrow plasma of patients with leukaemia and its gene expression in leukaemic blast cells. 855 73

Hepatocyte growth factor (HGF) stimulates cell proliferation, differentiation and migration by binding to its receptor, MET R. Whether the HGF/MET R axis plays an important regulatory role in human haemopoietic cell growth is an unresolved issue. To investigate this situation, we employed several complementary strategies including RT-PCR, FACS analysis, and mRNA perturbation with oligodeoxynucleotides (ODN). We found that very primitive, FACS sorted, CD34+ Kit+ marrow mononuclear cells (MNC) failed to express RT-PCR detectable MET R mRNA. In contrast, MET R expression was easily detectable by RT-PCR in marrow stroma fibroblasts, in cells isolated from BFU-E and CFU-GM colonies, and in unselected normal MNC. Subsequent FACS analysis revealed that MET R protein was detectable on approximately 5% of the latter cells. HGF, at concentrations of 1-50 ng/ml, had no demonstrable effect on survival or cloning efficiency of normal CD34+ MNC in serum-free cultures. Antisense ODN mediated perturbation of MET R mRNA expression in normal CD34+ MNC, with FACS documented decline in protein expression, had no effect on the ability of these cells to give rise to haemopoietic colonies of any lineage. We also examined the biology of HGF/MET R expression in malignant haemopoietic cells. Using the strategies described above, we found that MET R mRNA was expressed in many human haemopoietic cell lines, and that the protein was expressed at high levels on HTLV transformed T lymphocytes. Wild-type CML and AML blast cells also expressed MET mRNA, and HGF was able to co-stimulate CFU-GM colony formation in approximately 20% of cases studied. Therefore, although the HGF/MET R axis appears to be dispensable for normal haemopoietic cell growth, it may play a role in the growth of malignant haemopoietic progenitor cells.
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PMID:Effect of hepatocyte growth factor on early human haemopoietic cell development. 935 29

Angiogenesis has been associated with the growth, dissemination, and metastasis of solid tumors. The aims of this study were to evaluate the vascularity and the levels of angiogenic factors in patients with acute and chronic leukemias and myelodysplastic syndromes (MDS). The numbers of blood vessels were measured in 145 bone marrow biopsies and the levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis growth factor-alpha (TNF-alpha), tumor growth factor-alpha (TGF-alpha), and hepatocyte growth factor (HGF) were determined in 417 plasma samples. Except for chronic lymphocytic leukemia (CLL), vascularity was significantly higher in all leukemias and MDS compared with control bone marrows. The highest number of blood vessels and largest vascular area were found in chronic myeloid leukemia (CML). VEGF, bFGF, and HGF plasma levels were significantly increased in acute myeloid leukemia (AML), CML, CLL, chronic myelomonocytic leukemia (CMML), and MDS. HGF, TNF-alpha, and bFGF but not VEGF were significantly increased in acute lymphoblastic leukemia (ALL). TNF-alpha levels were significantly increased in all diseases except for AML and MDS. No significant increase was found in TGF-alpha in any leukemia or MDS. The highest plasma levels of VEGF were in CML, and the highest plasma levels of bFGF were in CLL. The levels of HGF were highest in CMML. These data suggest that vascularity and angiogenic factors are increased in leukemias and MDS and may play a role in the leukemogenic process.
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PMID:Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. 1097 72

Increased angiogenic activity has been demonstrated in myelofibrosis with myeloid metaplasia (MMM), chronic myeloid leukemia (CML), and essential thrombocythemia (ET) by both bone marrow microvessel density evaluation and measurement of circulating angiogenic factors. MMM is probably the disease with the more pronounced angiogenesis among myeloproliferative disorders but the significance of this finding remains speculative since the angiogenic activity is not correlated with any of the clinical and laboratory features of the disease. Circulating serum levels of angiogenic factors such as vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) were found increased in MMM, CML and ET but the frequent thrombocytosis that accompanies these diseases could limit the interpretation of these data since platelets and megakaryocytes may be considered a major source at least for VEGF. However, CML patients treated with interferon were found to have lower VEGF and HGF levels than untreated or hydroxyurea-treated patients, thus suggesting a possible antiangiogenic mechanism of this drug. In addition, preliminary experiences with the antiangiogenic drug thalidomide have shown therapeutic activity in some myeloproliferative disorders.
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PMID:Angiogenesis in chronic myeloproliferative diseases. 1181 15

The present study evaluated the serum levels of known angiogenic factors and analysed their prognostic significance in patients with acute or chronic leukemia. Enzyme-linked immunosorbent assays (ELISAs) were performed to quantify the basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), tumor necrosis factor-alpha (TNF-alpha), angiogenin, and matrix metalloproteinase-9 (MMP-9) in stored samples obtained before treatment from patients with acute myeloid leukemia (AML; 30 patients), acute lymphoblastic leukemia (ALL; 10 patients), and chronic myelogenous leukemia (CML; 14 patients). The levels of VEGF, HGF, angiogenin, and MMP-9 were all significantly higher in patients with CML than in healthy individuals. The HGF levels were also higher in patients with AML than in healthy individuals, plus there was a significant correlation between the HGF level and the white blood cell count, monocyte count, and serum level of lactate dehydrogenase (LDH) in patients with AML. In a univariate analysis, age and HGF level were both found to be significant parameters predictive for an achievement of complete remission (CR) in patients with AML. Meanwhile, in a multivariate analysis using a logistic regression model, the HGF level was the only parameter strongly predictive for CR (P=0.047). The leukemia-free survival (LFS) rate for AML patients with a lower HGF concentration was better than that for AML patients with a higher HGF concentration (1 year LFS rates=75.0% vs. 37.5%, P=0.065). The HGF concentration was an independent prognostic factor for an achievement of CR, plus higher HGF concentrations were associated with a lower survival in patients with AML.
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PMID:Clinical implications of angiogenic factors in patients with acute or chronic leukemia: hepatocyte growth factor levels have prognostic impact, especially in patients with acute myeloid leukemia. 1601 34

Mesenchymal stem cells (MSCs) have emerged as excellent candidates for clinical application because of their capabilities of differentiating into multiple mesenchymal lineages and supporting hematopoiesis. Recently, MSCs have gained further interests after the demonstration of an immunosuppressive role. However, it is still unclear whether the immunosuppressive capability of MSCs will be altered with disease state. In this study, we obtained and expanded MSCs from bone marrow of patients with chronic myeloid leukemia (CML). Our results showed that MSCs derived from CML do not express costimulatory molecules CD40, CD80, and CD86. When MSCs derived from CML were added back to T cells stimulated by mitogens, a significant inhibition of T-cell proliferation was evident. MSCs differentiated into various mesenchymal lineages did not alter their immunosuppressive effect on T-cell proliferation. A significant T-cell inhibition was found in a transwell system, in which cell-cell contact between MSCs and effector cells was prevented. Furthermore, we found that transforming growth factor beta1 (TGF beta1) and hepatocyte growth factor (HGF) were major mediators of T-cell suppression by MSCs derived from CML. These results demonstrated that autologous MSCs derived from CML could effectively suppress T-cell proliferation.
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PMID:Immunosuppressive properties of mesenchymal stem cells derived from bone marrow of patients with chronic myeloid leukemia. 1882 Dec 19

Chronic myeloid leukemia (CML) is a hematopoietic neoplasm characterized by the Philadelphia chromosome and the related BCR-ABL1 oncoprotein. Acceleration of CML is usually accompanied by basophilia. Several proangiogenic molecules have been implicated in disease acceleration, including the hepatocyte growth factor (HGF). However, little is known so far about the cellular distribution and function of HGF in CML. We here report that HGF is expressed abundantly in purified CML basophils and in the basophil-committed CML line KU812, whereas all other cell types examined expressed only trace amounts of HGF or no HGF. Interleukin 3, a major regulator of human basophils, was found to promote HGF expression in CML basophils. By contrast, BCR-ABL1 failed to induce HGF synthesis in CML cells, and imatinib failed to inhibit expression of HGF in these cells. Recombinant HGF as well as basophil-derived HGF induced endothelial cell migration in a scratch wound assay, and these effects of HGF were reverted by an anti-HGF antibody as well as by pharmacologic c-Met inhibitors. In addition, anti-HGF and c-Met inhibitors were found to suppress the spontaneous growth of KU812 cells, suggesting autocrine growth regulation. Together, HGF is a BCR-ABL1-independent angiogenic and autocrine growth regulator in CML. Basophils are a unique source of HGF in these patients and may play a more active role in disease-associated angiogenesis and disease progression than has so far been assumed. Our data also suggest that HGF and c-Met are potential therapeutic targets in CML.
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PMID:Identification of basophils as a major source of hepatocyte growth factor in chronic myeloid leukemia: a novel mechanism of BCR-ABL1-independent disease progression. 2290 75

Chronic myeloid leukemia (CML) is a hematopoietic stem-cell disorder which proliferates due to abnormal growth of basophil cells. Several proangiogenic molecules have been reported to be associated in CML progression, including the hepatocyte growth factor (HGF). However, detail mechanism about the cellular distribution and function of HGF in CML is yet to be revealed. The proliferation of hematopoietic cells are regulated by some of the growth factors like interleukin 3 (IL-3), IL-6, erythropoietin, thrombopoietin, etc. In this study IL-6 pathways have been taken into consideration which induces JAK/STAT and MAPK pathways to decipher the CML progression stages. An attempt has been made to model these pathways with the help of ordinary differential equations (ODEs) and estimating unknown parameters through fminsearch optimization algorithm. Some of the specific component like STAT3, of the pathway has been analyzed in detail and their role in CML progression has been elucidated. The roles of STAT3 inhibitors into the treatment of CML have been thoroughly studied and optimum concentration of the inhibitors have been predicted.
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PMID:Effect of STAT3 inhibitor in chronic myeloid leukemia associated signaling pathway: a mathematical modeling, simulation and systems biology study. 2833 Jan 11

Chronic myeloid leukaemia (CML) is a hematopoietic neoplasm defined by the chromosome translocation t(9;22) and the related oncogene, BCR-ABL1. In most patients, leukaemic cells can be kept under control using BCR-ABL1-targeting drugs. However, many patients relapse which remains a clinical challenge. In particular, patients with advanced (accelerated or blast phase) CML have a poor prognosis. So far, little is known about molecular and cellular interactions and features that contribute to disease progression and drug resistance in CML. One key prognostic factor at diagnosis is marked basophilia. However, although basophils are well-known multifunctional effector cells, their impact in CML remains uncertain. In this article, we discuss the potential role of basophils as active contributors to disease evolution and progression in CML. In particular, basophils serve as a unique source of inflammatory, angiogenic and fibrogenic molecules, such as vascular endothelial growth factor or hepatocyte growth factor. In addition, basophils provide vasoactive substances, like histamine as well as the cytokine-degrading enzyme dipeptidyl-peptidase IV which may promote stem cell mobilization and the extramedullary spread of stem and progenitor cells. Finally, basophils may produce autocrine growth factors for myeloid cells. Understanding the role of basophils in CML evolution and progression may support the development of more effective treatment concepts.
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PMID:The underestimated role of basophils in Ph+ chronic myeloid leukaemia. 3001 47

The RNA-binding protein Musashi 2 (MSI2) has emerged as an important regulator in cancer initiation, progression, and drug resistance. Translocations and deregulation of the MSI2 gene are diagnostic of certain cancers, including chronic myeloid leukemia (CML) with translocation t(7;17), acute myeloid leukemia (AML) with translocation t(10;17), and some cases of B-precursor acute lymphoblastic leukemia (pB-ALL). To better understand the function of MSI2 in leukemia, the mRNA targets that are bound and regulated by MSI2 and their MSI2-binding motifs need to be identified. To this end, using photoactivatable ribonucleoside cross-linking and immunoprecipitation (PAR-CLIP) and the multiple EM for motif elicitation (MEME) analysis tool, here we identified MSI2's mRNA targets and the consensus RNA-recognition element (RRE) motif recognized by MSI2 (UUAG). Of note, MSI2 knockdown altered the expression of several genes with roles in eukaryotic initiation factor 2 (eIF2), hepatocyte growth factor (HGF), and epidermal growth factor (EGF) signaling pathways. We also show that MSI2 regulates classic interleukin-6 (IL-6) signaling by promoting the degradation of the mRNA of IL-6 signal transducer (IL6ST or GP130), which, in turn, affected the phosphorylation statuses of signal transducer and activator of transcription 3 (STAT3) and the mitogen-activated protein kinase ERK. In summary, we have identified multiple MSI2-regulated mRNAs and provided evidence that MSI2 controls IL6ST activity that control oncogenic signaling networks. Our findings may help inform strategies for unraveling the role of MSI2 in leukemia to pave the way for the development of targeted therapies.
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PMID:Transcriptome-wide analysis uncovers the targets of the RNA-binding protein MSI2 and effects of MSI2's RNA-binding activity on IL-6 signaling. 3012 42


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