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)

The product of the dek oncogene is the 43-kDa DEK nuclear protein. DEK was first identified in a fusion with the CAN nucleoporin protein in a specific subtype of acute myelogenous leukemia. DEK has also been shown to be an autoantigen in patients with pauciarticular onset juvenile rheumatoid arthritis. Further, the last 65 amino acids of DEK can partially reverse the mutation-prone phenotype of cells from patients with ataxia-telangiectasia. However, in spite of these significant disease associations, the function of DEK has remained unclear. The HIV-2 peri-ets (pets) site is a TG-rich element found between the two Elf-1 binding sites in the HIV-2 enhancer. The pets element mediates transcriptional activation whether the enhancer is stimulated by phorbol 12-myristate 13-acetate (PMA) alone, phytohemagluttinin (PHA) alone, PMA plus PHA, soluble antibodies to the T cell receptor, immobilized antibodies to the T cell receptor, or by antigen. Previously, we purified and characterized the pets factor, demonstrating that it is a 43-kDa nuclear protein. We now describe the identification of DEK as this 43-kDa pets factor. Using a modified Southwestern screening procedure, we find that DEK can recognize the pets element. We demonstrate the ability of recombinant DEK to bind specifically to the pets site using the electrophoretic mobility shift assay (EMSA) and DNase I footprinting. "Supershift" EMSA further confirms that DEK is the dominant protein binding to the pets site in T cell extracts. Our findings show that DEK is a site-specific DNA binding protein that is likely involved in transcriptional regulation and signal transduction. This has implications for multiple pathogenic processes, including hematologic malignancies, arthritis, ataxia-telangiectasia, and AIDS caused by HIV-2.
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PMID:DEK, an autoantigen involved in a chromosomal translocation in acute myelogenous leukemia, binds to the HIV-2 enhancer. 905 Aug 61

There is strong clinical and epidemiological evidence that ionizing radiation can cause leukemia by inducing DNA damage. This crucial initiation event is believed to be the result of random DNA breakage and misrepair, whereas the subsequent steps, promotion and progression, must rely on mechanisms of selective pressure to provide the expanding leukemic population with its proliferative/renewal advantage. To investigate the susceptibility of human cells to external agents at the genetic recombination stage of leukemogenesis, we subjected two hematopoietic cell lines, KG1 and HL60, to high doses of gamma-irradiation. The irradiation induced the formation of fusion genes characteristic of leukemia in both cell lines, but at a much higher frequency in KG1 than in HL60. In KG1 cells, the AML1-ETO hybrid gene [associated with the t(8;21) translocation of acute myeloid leukemia] occurred significantly more often than the BCR-ABL [associated with t(9;22) chronic myeloid leukemia] or the DEK-CAN [associated with t(6;9) acute myeloid leukemia] fusion genes. These findings support the notion that ionizing radiation can directly generate leukemia-specific fusion genes but emphasize the differing susceptibility of different cell populations and the differing frequency with which the various fusion genes are formed. The selectivity observed at the primary level of gene fusion formation may explain at least in part the differential risk for development of some but not other forms of leukemia after high-dose radiation exposure.
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PMID:Selective induction of leukemia-associated fusion genes by high-dose ionizing radiation. 945 83

The human CAN gene was first identified as a target of t(6;9)(p23;q34), associated with acute myeloid leukemia and myelodysplastic syndrome, which results in the expression of a DEK-CAN fusion gene. CAN, also called NUP214, is a nuclear pore complex (NPC) protein that contains multiple FG-peptide sequence motifs. It interacts at the NPC with at least two other proteins, the nucleoporin NUP88 and hCRM1 (exportin 1), which was recently shown to function as a nuclear export receptor. Depletion of CAN in knockout mouse embryonic cells results in cell cycle arrest in G2, followed by inhibition of nuclear protein import and a block of mRNA export. We overexpressed CAN and DEK-CAN in U937 myeloid precursor cells. DEK-CAN expression did not interfere with terminal myeloid differentiation of U937 cells, whereas CAN-overexpressing cells arrested in G0, accumulated mRNA in their nuclei, and died in an apoptotic manner. Interestingly, we found that hCRM1 and import factor p97/importin beta colocalized with the ectopically expressed CAN protein, resulting in depletion of both factors from the NPC. Overexpression of the C-terminal FG-repeat region of CAN, which contains the binding site for hCRM1, caused sequestering of hCRM1 in the nucleoplasm and was sufficient to inhibit cell growth and to induce apoptosis. These results confirm that CAN plays a crucial role in nucleocytoplasmic transport and imply an essential role for hCRM1 in cell growth and survival.
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PMID:Overexpression of the nucleoporin CAN/NUP214 induces growth arrest, nucleocytoplasmic transport defects, and apoptosis. 948 38

Genes encoding the Phe-Gly (FG) repeat-containing nucleoporins NUP98 and CAN/NUP214 are at the breakpoints of several chromosomal translocations associated with human acute myeloid leukemia (AML), but their role in oncogenesis is unclear. Here we demonstrate that the NUP98-HOXA9 fusion gene encodes two nuclear oncoproteins with either 19 or 37 NUP98 FG repeats fused to the DNA binding and PBX heterodimerization domains of the transcription factor HOXA9. Both NUP98-HOXA9 chimeras transformed NIH 3T3 fibroblasts, and this transformation required the HOXA9 domains for DNA binding and PBX interaction. Surprisingly, the FG repeats acted as very potent transactivators of gene transcription. This NUP98-derived activity is essential for transformation and can be replaced by the bona fide transactivation domain of VP16. Interestingly, FG repeat-containing segments derived from the nucleoporins NUP153 and CAN/NUP214 functioned similarly to those from NUP98. We further demonstrate that transactivation by FG repeat-rich segments of NUP98 correlates with their ability to interact functionally and physically with the transcriptional coactivators CREB binding protein (CBP) and p300. This finding shows, for the first time, that a translocation-generated fusion protein appears to recruit CBP/p300 as an important step of its oncogenic mechanism. Together, our results suggest that NUP98-HOXA9 chimeras are aberrant transcription factors that deregulate HOX-responsive genes through the transcriptional activation properties of nucleoporin-specific FG repeats that recruit CBP/p300. Indeed, FG repeat-mediated transactivation may be a shared pathogenic function of nucleoporins implicated human AML.
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PMID:CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity. 985 99

The mechanism underlying the cytotoxicity mediated by a human CD4(+) cytotoxic T-lymphocyte (CTL) clone directed against a peptide derived from the acute myelogenous leukemia-associated fusion protein, DEK-CAN, was investigated. A DEK-CAN fusion peptide-specific CD4(+) Th0 CTL clone, designated HO-1, was established from the peripheral blood lymphocytes of a healthy individual. HO-1 exerted direct but not "innocent bystander" cytotoxicity within 2 hours. The cytotoxicity mediated by HO-1 was completely Ca2+-dependent. Because HO-1 lysed peptide-loaded Fas-deficient target cells derived from a patient with a homozygous Fas gene mutation, its cytotoxicity appeared to be mediated by a Fas-independent pathway. In addition, its cytotoxicity was only partially inhibited by treatment with concanamycin A and strontium ions, which are inhibitors of the perforin-based cytotoxic pathway. Although membrane-bound type of tumor necrosis factor-alpha (TNF-alpha) was expressed on HO-1, an anti-TNF-alpha antibody had no effect on HO-1-mediated cytotoxicity. HO-1 expressed mRNA for apoptosis-inducing mediators, including perforin, granzyme B, Fas ligand, TNF-alpha, and lymphotoxin; however, no DNA fragmentation was detected in target cells incubated with HO-1 by 5-[125I]Iodo-2'-deoxyuridine release assay and agarose gel electrophoresis of DNA. Although it has been suggested that the Fas/Fas ligand system is the main pathway by which CD4(+) CTL-mediated cytotoxicity is exerted in murine systems, HO-1 produced peptide-specific and HLA-restricted cytotoxicity via a Fas-independent and nonapoptotic pathway. The present study thus describes a novel mechanism of cytotoxicity mediated by CD4(+) CTL.
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PMID:Fas-independent and nonapoptotic cytotoxicity mediated by a human CD4(+) T-cell clone directed against an acute myelogenous leukemia-associated DEK-CAN fusion peptide. 992 Aug 42

The mammalian protein DEK has been implicated in multiple cellular processes, including transcriptional regulation, mRNA processing, and chromatin remodeling, and is associated with a number of clinical autoimmune and neoplastic conditions. The connection between DEK and cancer exists at multiple levels: (a) the t(6;9) chromosomal translocation that characterizes a subtype of acute myelogenous leukemia cases results in the formation of a DEK-CAN fusion oncoprotein; (b) a fragment of dek cDNA is capable of partially reversing the radiation-sensitive phenotype of fibroblasts cultured from ataxia-telangiectasia patients; and (c) increased levels of dek mRNA have been found to be associated with hepatocellular carcinoma, glioblastoma, and melanoma. Despite the growing list of cancer subtypes with a connection to DEK, the factors that mediate its expression have yet to be characterized. Here we undertake the analysis of DEK regulation by mapping the discrete elements within the proximal promoter that are responsible for constitutive transcription of dek in transformed cells. We find that functional elements include an inverted CCAAT box and a YY1 consensus binding site, and the introduction of point mutations into these sites markedly diminishes transcriptional activity. In addition, we identify the transcriptional activator NF-Y as a member of the CCAAT-binding complex, and verify binding of the transcription factor YY1 at its consensus site in the dek promoter. The discovery of NF-Y and YY1 as regulatory determinants of DEK expression is consistent with the well-documented roles of these two factors in cellular proliferation and transformation.
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PMID:YY1 and NF-Y binding sites regulate the transcriptional activity of the dek and dek-can promoter. 1248 38

MLL rearrangements in acute myeloid leukemia (AML) include translocations and intragenic abnormalities such as internal duplication and breakage induced by topoisomerase II inhibitors. In adult AML, FLT3 internal tandem duplications (ITDs) are more common in cases with MLL intragenic abnormalities (33%) than those with MLL translocation (8%). Mutation/deletion involving FLT3 D835 are found in more than 20% of cases with MLL intragenic abnormalities compared with 10% of AML with MLL translocation and 5% of adult AML with normal MLL status. Real-time quantification of FLT3 in 141 cases of AML showed that all cases with FLT3 D835 express high level transcripts, whereas FLT3-ITD AML can be divided into cases with high-level FLT3 expression, which belong essentially to the monocytic lineage, and those with relatively low-level expression, which predominantly demonstrate PML-RARA and DEK-CAN. FLT3 abnormalities in CBF leukemias with AML1-ETO or CBFbeta-MYH11 were virtually restricted to cases with variant CBFbeta-MYH11 fusion transcripts and/or atypical morphology. These data suggest that the FLT3 and MLL loci demonstrate similar susceptibility to agents that modify chromatin configuration, including topoisomerase II inhibitors and abnormalities involving PML and DEK, with consequent errors in DNA repair. Variant CBFbeta-MYH11 fusions and bcr3 PML-RARA may also be initiated by similar mechanisms.
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PMID:FLT3 and MLL intragenic abnormalities in AML reflect a common category of genotoxic stress. 1279 58

We report a 38-year-old woman with t(6;9) acute myeloid leukemia who relapsed with localized leukemic cell growth in the bone marrow after she had undergone allogeneic bone marrow transplantation. The localized cell growth was first recognized by an apparent discrepancy in the DEK-CAN fusion transcript levels between the aspirates from the left and right iliac bone marrow. Magnetic resonance imaging of the iliac bone revealed localized cell accumulation in the left side. The nonhomogeneous and localized leukemic cell growth in this case may have been due to the graft-versus-leukemia effect following allogeneic transplantation with donor lymphocyte infusion. Serial monitoring of molecular markers for leukemia at different sites or magnetic resonance imaging of the bone marrow may be of value in detecting this type of relapse.
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PMID:Localized relapse in bone marrow in a posttransplantation patient with t(6;9) acute myeloid leukemia. 1284 93

The KG-1 cell line, established from bone marrow cells of a patient with erythroleukemia evolving to acute myelogenous leukemia, and its less differentiated variant, KG-1a, are widely used in research worldwide. However, to our knowledge, neither cell line was studied by use of molecular-cytogenetic techniques such as spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH). Our G-banding, SKY, and FISH analyses revealed a complex karyotype with a pseudodiploid modal chromosome number in both the KG-1 and KG-1a cell lines. The lines shared several identical structural aberrations, including der(4)t(4;8), del(7q), der(8)t(8;12), idic(8)(p11), der(17)t(5;17), and der(20)t(12;20), but also differed with regard to other chromosome rearrangements. In contrast to KG-1, the KG-1a line lost one of the two copies of idic(8)(p11) present in KG-1 cells and gained a der(8;22)(q24;q13), an i(11)(q10), and a der(19)t(14;19)(q13;q13.4). Notably, we have shown that the KG-1 cells harbor a partial hexasomy of the long arm of chromosome 8, which may explain in part the previously reported significantly higher rate of formation of the AML1-ETO fusion gene in KG-1 cells subjected to high-dose gamma irradiation compared with the rates of formation of the BCR-ABL or the DEK-CAN fusion gene. Our detailed description of chromosome rearrangements in KG-1 and KG-1a will be useful for the cytogenetic authentication of the lines, and provide clues as to the regions of the genome that could be studied further to explain the differences in phenotypic properties between KG-1 and KG-1a cells.
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PMID:Molecular cytogenetic characterization of the KG-1 and KG-1a acute myeloid leukemia cell lines by use of spectral karyotyping and fluorescence in situ hybridization. 1450 99

Following induction chemotherapy for acute myeloid leukaemia (AML), sensitive determination of minimal residual disease (MRD) in patients achieving complete remission (CR) should enable the detection of early relapse and allow intervention at a more favourable stage than at overt relapse. We have determined the expression levels of the Wilms' tumour gene (WT1) by real-time quantitative polymerase chain reaction (RQ-PCR) in peripheral blood and bone marrow in 133 newly diagnosed AML patients and compared them with those in healthy volunteers. At diagnosis, the WT1 level exceeded normal expression in 118 of 133 (89%) patients, and was high enough to allow for detection of a WT1 decrease of least 1000-fold in 98 of 133 (74%) patients following induction therapy. Concomitant monitoring of fusion transcripts (PML-RARalpha, AML1-ETO, MLL-MLL, CBFbeta-MYH11, or DEK-CAN) in 38 patients identified different relationships between WT1 and fusion transcript levels, the AML1-ETO group showing remarkably low levels of WT1 compared with fusion transcript. In 32 patients analysed longitudinally there was close concordance between relapse and increased WT1 levels. Parallel longitudinal monitoring of WT1 and fusion transcript showed close correlation in 18 of 18 patients. We conclude that WT1 expression by RQ-PCR may be employed as a tool to detect MRD in the majority of fusion transcript-negative AML patients.
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PMID:WT1 gene expression: an excellent tool for monitoring minimal residual disease in 70% of acute myeloid leukaemia patients - results from a single-centre study. 1514 74


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