Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hematopoiesis is a complex process involving hematopoietic stem cell (HSC) self-renewal and lineage commitment decisions that must continue throughout life. Establishing a reproducible technique that allows for the long-term ex vivo expansion of human HSCs and maintains self-renewal and multipotential differentiation will allow us to better understand these processes, and we report the ability of the leukemia-associated AML1-ETO fusion protein to establish such a system. AML1-ETO-transduced human CD34+ hematopoietic cells routinely proliferate in liquid culture for more than 7 months, remain cytokine dependent for survival and proliferation, and demonstrate self-renewal of immature cells that retain both lymphoid and myeloid potential in vitro. These cells continue to express the CD34 cell surface marker and have ongoing telomerase activity with maintenance of telomere ends, however they do not cause leukemia in nonobese diabetic-severe combined immunodeficiency (NOD/SCID) mice. Identification of the signaling pathways that are modulated by AML1-ETO and lead to the self-renewal of immature human progenitor cells may assist in identifying compounds that can efficiently expand human stem and progenitor cells ex vivo.
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PMID:Maintaining the self-renewal and differentiation potential of human CD34+ hematopoietic cells using a single genetic element. 1294 95

Oncogenic activity is often associated with altered intracellular protein localization and with specific gains of function, e.g., kinase activity. We propose, that intracellular redirection of oncogenic proteins towards novel targets can be used to specifically kill tumor cells. For example, an oncogenic kinase could be redirected to activate an apoptosis inducing protein. This redirection approach offers the advantages of high specificity (the oncogene is restricted to tumor cells) and potentially high activity since it makes use of the intrinsic functions of the oncogene. Also, the oncogene is not only functionally inhibited but it is turned against the cancer cell. Activity and specificity of the redirection therapy approach were demonstrated in AML1-ETO positive leukemia cells. A recombinant protein redirected the transcriptionally inhibitory AML1-ETO protein to essential proliferation-associated promoters. As a result, leukemia cells were inhibited with high effectivity and specificity. This approach can be utilized to target a wide variety of human cancers.
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PMID:Redirection of oncoproteins to kill cancer cells. 1450 68

The regulation of graft-versus-host disease (GVHD) and graft-versus-leukemia/tumor (GVL/T) effect is the most important issue in allogeneic stem cell transplantation. Although it is very difficult to separate GVHD and GVL/T, however, we should try to find the way to suppress GVHD and induce GVL/T at the same time. From that point of view, the induction of CTL against minor histocompatibility antigens such as HA-1 and tumor specific antigens such as BCR-ABL chimeric protein may be useful. Also, the new concept of alloreactive NK cells which have inhibitory NK cell receptor seem to be interesting to regulate GVHD and GVL/T. Further study is needed to establish new allogeneic cell therapy to obtain the clinical improvement.
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PMID:[Target antigens for graft-versus-host disease (GVHD) and graft-versus-leukemia/tumor (GVL/T)]. 1451 17

Cellular and systemic O(2) concentrations are tightly regulated to maintain delicate oxygen homeostasis. Although the roles of hypoxia in solid tumors have been widely studied, few studies were reported regarding the possible effects of hypoxia on leukemic cells. Here, we showed for the first time that low concentrations of cobalt chloride (CoCl(2)), a hypoxia-mimicking agent, and 2-3% O(2) triggered differentiation of various subtypes of human acute myeloid leukemic (AML) cell lines, including NB4, U937 and Kasumi-1 cells, respectively, from M3, M5 and M2b-type AML, but CoCl(2) did not modulate AML subtype-specific fusion proteins promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) and AML1-ETO. Treatment with CoCl(2) also induced primary leukemic cells from some AML patients to undergo differentiation. Similar to what occurs in solid tumor cells, CoCl(2)-mimicked hypoxia also increased the level of hypoxia-inducible factor (HIF)-1alpha protein and its DNA-binding activity in leukemic cells. The CoCl(2) induction of HIF-1alpha protein and its DNA-binding activity were inhibited by 3-morpholinosydnonimine, which also blocked CoCl(2)-induced cell differentiation in leukemic cells. These results provide an insight into a possible link of hypoxia or HIF-1alpha and leukemic cell differentiation, and are possibly of significance to explore clinical potentials of hypoxia or hypoxia-mimicking agents and novel target-based drugs for differentiation therapy of leukemia.
Leukemia 2003 Nov
PMID:Cobalt chloride and low oxygen tension trigger differentiation of acute myeloid leukemic cells: possible mediation of hypoxia-inducible factor-1alpha. 1452 74

The t(12;21)(p12;q22) is the most frequent chromosomal rearrangement observed in acute lymphoblastic leukaemia (ALL) and is associated with favourable prognosis and good response to initial treatment. The translocation-Ets-leukaemia (TEL) and AML1 genes are very often involved in chromosomal translocations in haematopoietic malignancies. This review presents the structure, roles of TEL and AML1 genes, and their proteins in haematopoiesis and in leukaemiogenesis as well. Aspects such as: the mechanism of translocation t(12;21)(p12;q22), function of TEL/AML1 fusion gene and chimeric protein, clinical significance of this abnormality and methods allowing to detect this translocation and its transcript are also discussed in this paper.
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PMID:Mechanism, detection and clinical significance of the reciprocal translocation t(12;21)(p12;q22) in the children suffering from acute lymphoblastic leukaemia. 1463 78

The acute myeloid leukemia (AML)-associated translocation products AML1-ETO, PML-retinoic acid receptor alpha (RARalpha), and PLZF-RARalpha encode aberrant transcription factors. Several lines of evidence suggest similar pathogenetic mechanisms for these fusion proteins. We used high-density oligonucleotide arrays to identify shared target genes in inducibly transfected U937 cells expressing AML1-ETO, PML-RARalpha, or PLZF-RARalpha. All three fusion proteins significantly repressed the expression of 38 genes and induced the expression of 14 genes. Several of the regulated genes were associated with Wnt signaling. One of these, plakoglobin (gamma-catenin), was induced on the mRNA and protein level by all three fusion proteins. In addition, primary AML blasts carrying one of the fusion proteins significantly overexpressed plakoglobin. The plakoglobin promoter was cloned and shown to be induced by AML1-ETO, with promoter activation depending on the corepressor and histone deacetylase binding domains. The induction of plakoglobin by AML fusion proteins led to downstream signaling and transactivation of TCF- and LEF-dependent promoters, including the c-myc promoter, which was found to be bound by plakoglobin in vivo after AML1-ETO expression. beta-Catenin protein levels and TCF and LEF target genes such as c-myc and cyclin D1 were found to be induced by the fusion proteins. On the functional level, a dominant negative TCF inhibited colony growth of AML1-ETO-positive Kasumi cells, whereas plakoglobin transfection into myeloid 32D cells enhanced proliferation and clonal growth. Injection of plakoglobin-expressing 32D cells into syngeneic mice accelerated the development of leukemia. Transduction of plakoglobin into primitive murine hematopoietic progenitor cells preserved the immature phenotype during colony growth, suggesting enhanced self-renewal. These data provide evidence that activation of Wnt signaling is a common feature of several balanced translocations in AML.
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PMID:Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells. 1502 77

The protease of murine leukemia virus (MLV) was cloned into pMal-c2 vector, expressed in fusion with maltose-binding protein (MBP), and purified to homogeneity after Factor Xa cleavage of the chimeric protein. Substantial degradation of the fusion protein was observed during expression, which severely diminished the yield. The degree of degradation of the fusion protein was even more pronounced when a single-chain form of the MLV protease was cloned after the gene coding for MBP. To increase the yield, a hexahistidine tag with an additional Factor Xa cleavage site was cloned after the protease and nickel chelate affinity chromatography was used as the first purification step. The modified procedure resulted in substantially higher yield as compared to the original procedure. The degradation of hexahistidine-tagged active site mutant MLV protease was very low and comparable to that obtained with hexahistidine-tagged MBP, but purified MLV protease alone was not able to degrade purified MBP, suggesting that during expression the active MLV protease may activate bacterial proteases which appear to be responsible for the degradation of the fusion proteins.
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PMID:Expression of the murine leukemia virus protease in fusion with maltose-binding protein in Escherichia coli. 1503 67

The AML1-ETO fusion has been associated with up to 40% of acute myeloid leukaemia French-American-British classified M2 cases. This chimaeric protein interferes with normal AML1 function and disrupts critical transcriptional regulation of haematopoiesis. Current evidence suggests that AML1-ETO alone is insufficient to induce leukaemia, but rather is a co-operating event in leukaemogenesis. We developed a pluripotent murine haematopoietic stem cell line expressing the AML1-ETO fusion protein that displays in vitro and in vivo properties consistent with a preleukaemic state, including inhibition of terminal granulocytic differentiation in vitro and the development of non-lymphoid leukaemias in vivo. This cell line represents a potential platform for the introduction and in vitro rapid screening of candidate genes thought to co-operate with AML1-ETO in developing frank leukaemia.
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PMID:Establishment of a pluripotent preleukaemic stem cell line by expression of the AML1-ETO fusion protein in Notch1-immortalized HSCN1cl10 cells. 1508 16

Retroviral insertional mutagenesis in BXH2 mice commonly induces myeloid leukemias. One of the most frequently involved genes in experimental studies is Meis 1. In contrast to other genes in murine models, Meis 1 has not been affected by recurrent chromosomal translocations or point mutations in human leukemias. We found a constant downregulation of the Meis 1 gene mRNA in AML1-ETO acute myeloid leukemias and in those cases harboring in frame mutations in the bZIP domain of CEBPalpha. The absence of the Meis 1 mRNA was not caused by inactivating point mutations in the coding sequence. Promoter hypermethylation was present in more than half of the cases (9/14), including samples obtained from the widely employed Kasumi-1 cell line. Double treatment with 5-Aza-2'-deoxycytidine and trichostatin A of the Kasumi-1 cell line partially reverses Meis 1 inhibition. HoxA9 levels were also low. In a cell line model (U937 Tet AML1-ETO), AML1-ETO expression was not associated with Meis 1 suppression at 72 h. Nevertheless, Meis 1 repression is dependent on the AML1-ETO transcript levels in treated leukemic patients. Chimeric products that arise from chromosomal translocations may be associated with locus-specific epigenetic inactivation. It remains to be investigated when this methylation process is acquired and which are the basic mechanisms underlying these molecular events in AML1-ETO and CEBPalpha-mutated AML.
Leukemia 2004 Jul
PMID:MEIS 1 expression is downregulated through promoter hypermethylation in AML1-ETO acute myeloid leukemias. 1510 90

We review the therapeutic and preventive applications of a retinoid analog (vitamin A and its derivatives) for human cancers. Chemoprevention of cancer is an intervention in the carcinogenic process by chemical agents that block or reverse the malignant transformation of cells. Retinoids are prime candidates for cancer chemoprevention since cancer is characterized by abnormal growth with a lack of differentiation, which could be modified by retinoids. Retinoids exert their biological functions through nuclear receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR). A number of experimental and clinical studies have been performed in the past two decades with retinoids showing that they inhibit or reverse the carcinogenic process in some organs, including hematological malignancy as well as premalignant and malignant lesions in the oral cavity, head and neck, breast, skin and liver. We particularly focus upon the therapeutic application of all-trans RA (atRA) to acute promyelocytic leukemia (APL) and on the preventive approach to hepatocellular carcinoma (HCC) by a synthetic retinoid analog, acyclic retinoid. In both malignancies, malfunction of retinoid nuclear receptors is closely related to their carcinogenic process. In APL, a chromosomal translocation produces a chimeric protein between RAR alpha and a protein called promyelocyte leukemia protein (PML). PML-RAR alpha works as a dominant negative receptor in the leukemic cells, interfering with the normal function of RAR alpha and/or PML, which in turn results in the arrest of cell maturation at the stage of promyelocytes. Oral administration of atRA induces differentiation of promyelocytic leukemic cells to mature neutrophils, and leads to a high rates (over 90%) of complete remission. AtRA therapy has become standard in the treatment of APL. In the case of HCC, post-translational modification of RXR by phosphorylation impairs its function, which leads to uncontrolled cell growth. Acyclic retinoid suppresses the phosphorylation of RXR alpha, restores its function in the presence of its endogenous ligand, 9-cis RA, and thereby induces apoptosis of the cancer cells. Acyclic retinoid given orally successfully suppresses the development of second primary tumors in cirrhotic patients who undergo curative removal of preceding HCC. Eradication of (pre)malignant clones ('clonal deletion') from the liver is suggested as a mechanism of the chemopreventive effect. Further development of more effective retinoids as well as their use in combination with other classes of anticancer agents including immunopreventive drugs like interferons may provide strategies for cancer prevention.
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PMID:Retinoids in cancer chemoprevention. 1513 35


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