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Blood, 15 March 2007, Vol. 109, No. 6, pp. 2589-2596. Prepublished online as a Blood First Edition Paper on November 14, 2006; DOI 10.1182/blood-2006-02-004234. This Article Full Text Full Text (PDF) Supplemental Tables Supplemental Figures All Versions of this Article: blood-2006-02-004234v1 109/6/2589    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Irish, J. M. Articles by Gjertsen, B. T. Search for Related Content PubMed PubMed Citation Articles by Irish, J. M. Articles by Gjertsen, B. T. Related Collections Neoplasia Apoptosis Cell Cycle Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Flt3 Y591 duplication and Bcl-2 overexpression are detected in acute myeloid leukemia cells with high levels of phosphorylated wild-type p53 Jonathan M. Irish1, Nina Ånensen2, Randi Hovland3,4, Jørn Skavland2, Anne-Lise Børresen-Dale5, Øystein Bruserud2,6, Garry P. Nolan1, and Bjørn T. Gjertsen2,6 1 Department of Microbiology and Immunology, Baxter Laboratory of Genetic Pharmacology, Stanford University, Stanford, CA; 2 Institute of Medicine, Haematology Section, University of Bergen, Bergen, Norway; 3 Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway; 4 Proteomic Unit (PROBE), University of Bergen, Bergen, Norway; 5 Department of Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo, Norway; 6 Department of Internal Medicine, Haematology Section, Haukeland University Hospital, Bergen, Norway Loss or mutation of the TP53 tumor suppressor gene is not commonly observed in acute myeloid leukemia (AML), suggesting that there is an alternate route for cell transformation. We investigated the hypothesis that previously observed Bcl-2 family member overexpression suppresses wild-type p53 activity in AML. We demonstrate that wild-type p53 protein is expressed in primary leukemic blasts from patients with de novo AML using 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and phospho-specific flow cytometry. We found that p53 was heterogeneously expressed and phosphorylated in AML patient samples and could accumulate following DNA damage. Overexpression of antiapoptosis protein Bcl-2 in AML cells was directly correlated with p53 expression and phosphorylation on serine residues 15, 46, and 392. Within those patients with the highest levels of Bcl-2 expression, we identified a mutation in FLT3 that duplicated phosphorylation site Y591. The presence of this mutation correlated with greater than normal Bcl-2 expression and with previously observed profiles of potentiated STAT and MAPK signaling. These results support the hypothesis that Flt3-mediated signaling in AML enables accumulation of Bcl-2 and maintains a downstream block to p53 pathway apoptosis. Bcl-2 inhibition might therefore improve the efficacy of existing AML therapies by inactivating this suppression of wild-type p53 activity. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. W. Lee, E. R. Sharp, A. O'Mahony, M. G. Rosenberg, D. M. Israelski, G. P. Nolan, and D. F. Nixon Single-Cell, Phosphoepitope-Specific Analysis Demonstrates Cell Type- and Pathway-Specific Dysregulation of Jak/STAT and MAPK Signaling Associated with In Vivo Human Immunodeficiency Virus Type 1 Infection J. Virol., April 1, 2008; 82(7): 3702 - 3712. [Abstract] [Full Text] [PDF]

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