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)

DEK is a mammalian protein that has been implicated in the pathogenesis of autoimmune diseases and cancer, including acute myeloid leukemia, melanoma, glioblastoma, hepatocellular carcinoma, and bladder cancer. In addition, DEK appears to participate in multiple cellular processes, including transcriptional repression, mRNA processing, and chromatin remodeling. Sub-nuclear distribution of this protein, with the attendant functional ramifications, has remained a controversial topic. Here we report that DEK undergoes acetylation in vivo at lysine residues within the first 70 N-terminal amino acids. Acetylation of DEK decreases its affinity for DNA elements within the promoter, which is consistent with the involvement of DEK in transcriptional repression. Furthermore, deacetylase inhibition results in accumulation of DEK within interchromatin granule clusters (IGCs), sub-nuclear structures that contain RNA processing factors. Overexpression of P/CAF acetylase drives DEK into IGCs, and addition of a newly developed, synthetic, cell-permeable P/CAF inhibitor blocks this movement. To our knowledge, this is the first reported example of acetylation playing a direct role in relocation of a protein to IGCs, and this may explain how DEK can function in multiple pathways that take place in distinct sub-nuclear compartments. These findings also suggest that DEK-associated malignancies and autoimmune diseases might be amenable to treatment with agents that alter acetylation.
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PMID:p300/CBP-associated factor drives DEK into interchromatin granule clusters. 1598 77

This study was aimed to explore the relationship of 6; 9 chromosome translocation with DEK-CAN fusion gene expression in patients with acute myeloid leukemia (AML) and its clinical significance. Chromosome specimens were prepared by routine method after short-term culture of bone marrow cells; karyotype analysis was performed by R banding technique; the expression of fusion gene DEK-CAN was analyzed by RT-nested-PCR in mononuclear cells of bone marrow or peripheral blood of 4 AML patients, for 3 patients received allo-BMT out of 4 patients the dynamic follow-up was performed. The results indicated that t (6; 9) (p23; q34) was confirmed by chromosome karyotype analysis in the four AML patients. The DEK-CAN fusion gene was found during in all four de novo, relapsed and CR patients (100%). And the expression of DEK-CAN fusion gene enhanced apparently in de novo and relapsed patients, and weakened in CR patient. DEK-CAN mRNA was found in the three patients during 1-24 months after allo-BMT. Clinical data showed 2 patients relapsed and died after CR for 1-24 months; the other two patients received allo-BMT got CR and still survive. It is concluded that DEK-CAN fusion gene is the molecular basis in pathogenesis of AML. The detection of DEK-CAN fusion gene is significant for diagnosis of AML, evaluation of curative effect, and predication of prognosis.
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PMID:[Analysis of DEK-CAN fusion gene expression in acute myeloid leukemia patients with 6; 9 chromosome translocation]. 1663 87

NPM1 gene mutations are the most frequent genetic lesion in the 60% of adult acute myeloid leukemias (AMLs) with normal karyotype and no evidence of typical fusion genes (BCR/ABL1, PML/RARA, AML1/ETO, CBFB/MYH11, DEK/CAN). Using direct sequencing we previously identified six different heterozygous mutants within exon 12 encoding the nucleophosmin C-terminus. Because of these mutations the shuttling protein nucleophosmin is aberrantly delocalized in the cytoplasm of leukemic cells (NPMc+). Here, we designed and tested a denaturing high-performance liquid chromatography (DHPLC) assay to detect NPM1 mutated variants. To assess specificity, sensitivity, reliability, and reproducibility, we analyzed DNA from 120 primary adult AMLs and compared DHPLC results with immunohistochemistry and sequencing. All electropherogram profiles in the 26 NPMc+ leukemias were different from the wild type, indicating 100% sensitivity. Sequencing categorized mutations A, B, and D, and all mutation A cases gave identical elution profiles. The other mutations showed typical chromatograms, with mutations B and D differing for one nucleotide. Elution profiles and sequencing also identified four new variants. Our results suggest that DHPLC detects NPM1mutations as well as direct sequencing and immunohistochemistry, providing a helpful approach in the diagnosis of NPMc+ AML.
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PMID:Denaturing high-performance liquid chromatography: a valid approach for identifying NPM1 mutations in acute myeloid leukemia. 1664 13

The proto-oncogene protein DEK has been implicated in the t(6;9) chromosomal translocation associated with a subtype of acute myelogenous leukemia (AML), which results in the formation of a DEK-CAN fusion protein. Histone acetylation is an important post-translational modification which is involved in transcriptional regulation. In this study, we report that the acidic domain containing protein DEK interacts with histones and exerts a potent inhibitory effect on both p300 and PCAF-mediated histone acetyltransferase activity and transcription. Using chromatin immunoprecipitation assays, we have demonstrated that the recruitment of DEK to the appropriate promoter induces the histone H3 and H4 hypoacetylation of chromatin. Collectively, our data illustrate the important regulatory role played by protein DEK in transcriptional regulation, and suggest that transcription-regulating acidic domain regions may play a role in leukemogenesis.
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PMID:Regulation of histone acetyltransferase activity of p300 and PCAF by proto-oncogene protein DEK. 1669 75

Deregulation of the retinoblastoma (pRB) tumor suppressor pathway associated with aberrant activity of E2F transcription factors is frequently observed in human cancer. Microarray based analyses have revealed a large number of potential downstream mediators of the tumor suppressing activity of pRB, including DEK, a fusion partner of CAN found in a subset of acute myeloid leukaemia (AML) patients carrying a (6; 9) translocation. Here we report that the expression of DEK is under direct control of E2F transcription factors. Chromatin immunoprecipitation assays show that the DEK promoter is bound by endogenous E2F in vivo. The DEK promoter is transactivated by E2F and mutation of E2F binding sites eliminates this effect. Expression levels of DEK in human tumors have been investigated by tissue micro array analysis. We find that DEK is overexpressed in many solid tumors such as colon cancer, larynx cancer, bladder cancer, and melanoma.
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PMID:DEK Expression is controlled by E2F and deregulated in diverse tumor types. 1672 Oct 57

Multiplex reverse transcription-polymerase chain reaction (M-RT-PCR) has been proved to possess great clinical potential for simultaneous screening of 29 chromosomal translocations in acute leukemia. To evaluate the clinical value of M-RT-PCR in hematologic malignancies, bone marrow samples from 90 patients with various hematologic malignancies, including 25 acute myelogenous leukemia (AML), 22 acute lymphoblastic leukemia (ALL), 27 chronic myelogenous leukemia (CML), 4 myeloproliferative diseases (MPD), 3 chronic lymphoblastic leukemia (CLL), 3 non-Hodgkin's lymphoma (NHL), 3 myelodysplastic syndrome (MDS), 2 multiple myeloma (MM) and 1 malignant histiocytosis (MH) were subjected to both M-RT-PCR and chromosome karyotypic analysis. Some of cases were subjected to follow-up examination of M-RT-PCR during the period of clinical complete remission (CR) for detection of minimal residual leukemia. In our hand, 12 of 29 chromosomal translocation transcripts including TEL/PDGFR, DEK/CAN, MLL/AF6, AML1/ETO, MLL/AF9, BCR/ABL, MLL/MLL, PML/RARu, TLS/ERG, E2A/HLF, EVI1 and HOXI1 were detected in 57 cases (63.3 %) of the 90 samples, which were in consistency with the results of karyotypic analysis. Furthermore, M-RT-PCR had also shown good clinical relevance when used as an approach to detect minimal residual leukemia. We concluded that M-RT-PCR could be used as an efficient and fast diagnostic tool not only in the initial diagnosis of hematologic malignancies but also in subsequent monitor of minimal residual leukemia.
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PMID:Multiplex reverse transcription-polymerase chain reaction for simultaneous screening of 29 chromosomal translocation in hematologic malignancies. 1735 82

Leukemia-specific chromosome translocations involving the nucleoporin CAN/NUP214 lead to expression of different fusion genes including DEK-CAN, CAN-ABL, and SET-CAN. DEK-CAN and CAN-ABL1 are associated with acute myeloid leukemia and T-cell acute lymphoblastic leukemia, respectively, whereas SET-CAN was identified in a patient with acute undifferentiated leukemia. In addition, SET is overexpressed in solid tumors of the breast, uterus, stomach, and rectum. Ectopic expression of SET-CAN inhibits vitamin-D(3)-induced differentiation of the human promonocytic U937cells, whereas ectopic SET expression induces differentiation. Here, we assessed the leukemogenic potential of SET-CAN in the hematopoietic system of transgenic mice. Although SET-CAN mice showed expansion of an early progenitor cell pool and partial depletion of lymphocytes, the animals were not leukemia-prone and did not show shortening of disease latency after retroviral tagging. This suggests that SET-CAN expression in acute undifferentiated leukemia might determine the primitive phenotype of the disease, whereas secondary genetic lesions are necessary for disease development. Surprisingly, SET-CAN mice developed spontaneous hyperplasia of the stomach mucosa, which coincided with overexpression of beta-catenin and vastly increased numbers of proliferating gastric mucosa cells, suggesting a role of SET-CAN in proliferation of certain epithelial cells.
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PMID:SET-CAN, the product of the t(9;9) in acute undifferentiated leukemia, causes expansion of early hematopoietic progenitors and hyperproliferation of stomach mucosa in transgenic mice. 1756 77

The t(6;9)(p22;q34) chromosomal translocation is found in a subset of patients with acute myeloid leukemia (AML). The translocation results in a fusion between the nuclear phosphoprotein DEK and the nucleoporin NUP214 (previously CAN). The mechanism by which the fusion protein DEK-NUP214 contributes to leukemia development has not been identified, and disruptions of normal cellular functions by DEK-NUP214 have previously not been described. In the present study, a novel effect of the DEK-NUP214 fusion protein is demonstrated. Our findings reveal a substantial increase in global protein synthesis in DEK-NUP214 expressing cells. Furthermore, we conclude that this effect is not the result of dysregulated transcription but merely due to increased translation. Consistent with the association with AML, the increased protein synthesis mediated by DEK-NUP214 is restricted to cells of the myeloid lineage. Analysis of potential mechanisms for regulating protein synthesis shows that expression of DEK-NUP214 correlates to the phosphorylation of the translation initiation protein, EIF4E. The present data provide evidence that increase of translational activity constitutes a mechanism by which the leukemogenic effect of DEK-NUP124 may be mediated.
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PMID:Identification of a novel and myeloid specific role of the leukemia-associated fusion protein DEK-NUP214 leading to increased protein synthesis. 1818 Nov 80

The human DEK protein has a long-standing association with carcinogenesis since the DEK gene was originally identified in the t(6:9) chromosomal translocation in a subtype of patients with acute myelogenous leukemia (AML). Recent studies have partly unveiled DEK's cellular functions including apoptosis inhibition in primary cells as well as cancer cells, determination of 3' splice site of transcribed RNA, and suppression of transcription initiation by polymerase II. It has been previously shown that the N-terminal region of DEK, spanning residues 68-226, confers important in vitro and in vivo functions of DEK, which include double-stranded DNA (ds-DNA) binding, introduction of constrained positive supercoils into closed dsDNA, and apoptosis inhibition. In this paper, we describe the three-dimensional structure of the N-terminal domain of DEK (DEKntd) as determined using solution NMR. The C-terminal part of DEKntd, which contains a putative DNA-binding motif (SAF/SAP motif), folds into a helix-loop-helix structure. Interestingly, the N-terminal part of DEKntd shows a very similar structure to the C-terminal part, although the N-terminal and the C-terminal part differ distinctively in their amino acid sequences. As a consequence, the structure of DEKntd has a pseudo twofold plane symmetry. In addition, we tested dsDNA binding of DEKntd by monitoring changes of NMR chemical shifts upon addition of dsDNAs. We found that not only the C-terminal part containing the SAF/SAP motif but the N-terminal part is also involved in DEKntd's dsDNA binding. Our study illustrates a new structural variant and reveals novel dsDNA-binding properties for proteins containing the SAP/SAF motif.
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PMID:Solution NMR structure of the N-terminal domain of the human DEK protein. 1822 28

Acute myelogenous leukemia (AML) with chromosomal translocation (6;9)(p23;q34) is a rare disease with poor prognosis and distinct clinical and morphologic features. t(6;9) results in a chimeric fusion gene between DEK (6p23) and CAN/NUP214 (9q34). FLT3-ITD mutation is one of the most frequent mutations in AML and correlates with poor clinical outcome. Prevalence of FLT3-ITD is as high as 70% among patients with t(6;9) AML, and patients with t(6;9) AML and FLT3-ITD mutations usually have higher white blood cell counts, higher bone marrow blasts, and significantly lower rates of complete remission. t(6;9) is most commonly associated with AML-FAB-M2 and is considered by some researchers to be a separate disease entity because of its distinct clinical and morphologic features and poor prognostic implication. Distinct morphologic features of this entity include marrow basophilia and myelodysplasia, and immunophenotypically, the blast cells are positive for CD9, CD13, CD33, and HLA-DR; are usually positive for CD45 and CD38; and may be positive for CD15, CD34, and terminal deoxynucleotidyl transferase.
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PMID:Acute myelogenous leukemia with t(6;9)(p23;q34) and marrow basophilia: an overview. 1897 25


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