Loss of expression of ZACIPLAGLI in diffuse large B-cell lymphoma is independent of promoter hypermethylation
Section of Genetics, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds, UK.Genes Chromosomes and Cancer (Impact Factor: 4.04). 05/2010; 49(5):480-6. DOI: 10.1002/gcc.20758
ZAC/PLAGL1 is a ubiquitously expressed, imprinted tumor suppressor gene located on 6q24, a chromosomal region that is frequently deleted in diffuse large B-cell lymphoma (DLBCL). Like p53, ZAC regulates cell cycle arrest and apoptosis concomitantly, and loss of expression is implicated in tumorigenesis in a variety of different cancers. In most tissues, ZAC transcription is monoallelic and driven by the paternal allele of promoter P1, which lies within a differentially methylated CpG island (DMR). In human blood cells, ZAC transcription is driven by promoter P2, which lies within an unmethylated CpG island and produces biallelic transcripts. Previous reports of epigenetic changes of ZAC in tumors have focused on P1, showing frequent loss of expression caused by paternal allele hypermethylation or loss of heterozygosity (LOH). As ZAC expression in normal B lymphocytes is derived from P2, in DLBCL we analyzed both promoters for gene expression, LOH and abnormal methylation. Loss of P2 transcription was observed in 8 of 11 lymphomas (73%), even though the P2 CpG island remained unmethylated. Three lymphomas showed evidence of LOH (23%), and abnormal methylation of the P1 DMR was observed in an additional four (31%), despite minimal P1 activity in normal B lymphocytes. These data indicate that downregulation of ZAC occurs in DLBCL, as in other cancers. However, unlike P1, transcriptional repression of P2 is not caused by hypermethylation of its associated CpG island in tumors. The mechanistic relationship between altered ZAC expression and epigenetic changes at its promoters thus appears more complex than previously supposed.
Conference Paper: Neural stator flux estimator with dynamical signal preprocessing[Show abstract] [Hide abstract]
ABSTRACT: This work presents a novel method of stator flux estimation for induction motor, using artificial neural networks. Proposed estimation scheme can be employed in any vector controlled drive, e.g. DTC (direct torque control) or SFOC (stator field oriented control) drive. It does not exploit pure integration, therefore there is no problem with drift and initial conditions. Moreover, it does not require any stator resistance adaptation algorithm. A multilayer perceptron is trained off-line to approximate stator flux space vector. The approximation space is spanned by stator voltages and currents preprocessed with different low-pass filters. The performance of the SFOC drive with the above stator flux estimator has been investigated in simulation. The results seem to be very promising. Developed estimator is quite insensitive to the stator resistance variations.
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ABSTRACT: Cytokine signaling pathways are frequent targets of oncogenic mutations in acute myeloid leukemia (AML), promoting proliferation and survival. We have previously shown that the transcription factor PLAGL2 promotes proliferation and cooperates with the leukemia fusion protein Cbfβ-SMMHC in AML development. Here, we show that PLAGL2 upregulates expression of the thrombopoietin receptor Mpl, using two consensus sites in its proximal promoter. We also show that Mpl overexpression efficiently cooperates with Cbfβ-SMMHC in development of leukemia in mice. Finally, we demonstrate that PlagL2-expressing leukemic cells show hyper-activation of Jak2 and downstream STAT5, Akt and Erk1/2 pathways in response to Thpo ligand. These results show that PlagL2 expression activates expression of Mpl in hematopoietic progenitors, and that upregulation of wild-type Mpl provides an oncogenic signal in cooperation with CBFβ-SMMHC in mice.
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ABSTRACT: ZAC/PLAGL1 is a novel imprinted tumor suppressor gene encoding an important inducer of cell cycle arrest and apoptosis, and found to be lost during tumorigenesis. We analyzed the significance of ZAC in the development of a rare, usually benign tumor of the adrenal gland: pheochromocytoma (PCC). Twenty-four PCCs were analyzed for the loss of the active nonimprinted allele of ZAC, and nine of the twenty-four PCCs were also assayed for expression of the protein. In thirteen of the cases, a paired nonmalignant tissue was available for analysis. Methylation-specific polymerase chain reaction revealed frequent (15 of 23, 65%) loss of unmethylated DNA in the imprinting control region of ZAC. Immunohistochemistry identified reduced ZAC expression in 56% (5 of 9) of the subset cases. Four of the five PCC cases where reduced expression of ZAC was observed were also positive for the loss of the active ZAC allele. Additionally, the loss of ZAC expression was also found to be frequent in a series of capillary hemangioblastomas and gliomas (6 of 6, 100%, and 17 of 27, 63%, respectively) examined for comparison. In conclusion, our study suggests the involvement of the imprinted ZAC gene in the pathogenesis of PCC.
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