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Blood, 1 April 2004, Vol. 103, No. 7, pp. 2744-2752. Prepublished online as a Blood First Edition Paper on December 4, 2003; DOI 10.1182/blood-2003-07-2280. This Article Full Text (PDF) All Versions of this Article: 2003-07-2280v1 103/7/2744    most recent Alert me when this article is cited Alert me if a correction is posted 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 Schwieger, M. Articles by Stocking, C. Search for Related Content PubMed PubMed Citation Articles by Schwieger, M. Articles by Stocking, C. Social Bookmarking                   What's this? Submitted July 8, 2003 Accepted November 16, 2003 A dominant-negative mutant of C/EBP, associated with acute myeloid leukemias, inhibits differentiation of myeloid and erythroid progenitors of man but not mouse Maike Schwieger, Juergen Loehler, Meike Fischer, Uwe Herwig, Daniel G Tenen, and Carol Stocking* Department of Molecular Pathology, Heinrich-Pette-Institut, Hamburg, Germany Department of Gynecology and Obstetrics, Albertinen Hospital, Hamburg, Germany Harvard Institutes of Medicine, Boston, MA, USA * Corresponding author; email: stocking{at}hpi.uni-hamburg.de. The CCAAT/enhancer binding protein alpha (C/EBP) is an essential transcription factor for granulocytic differentiation. C/EBP mutations are found in approximately 8% of acute myeloid leukemia (AML) patients. Most of these mutations occur in the N-terminal coding region, resulting in a frame-shift and the enhanced translation of a dominant-negative 30 kDa protein, which may be responsible for the differentiation block observed in AML. To test this hypothesis, we introduced a cDNA encoding a N-terminal mutated C/EBP(mut10) into primary hematopoietic progenitors using a retroviral vector. Expression of mut10 in human CD34+ cord blood cells dramatically inhibited differentiation of both myeloid and erythroid lineages. Immunohistochemical analysis demonstrated the co-expression of both myeloid and erythroid markers in the immature transformed cells. Surprisingly, mut10 did not block myelocytic differentiation in murine progenitors, but altered the differentiation kinetics and clonogenicity. Experiments were performed to confirmed that the differential effect of mut10 on murine and human progenitors was not due to species-specific differences in C/EBP protein sequences, expression levels, or inefficient targeting of relevant cells. Taken together, our results underline the intrinsic differences between hematopoietic controls in mouse and human and support the hypothesis that mutations in CEBPA are critical events in the disruption of myeloid differentiation in AMLs. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Schwieger, A. Schuler, M. Forster, A. Engelmann, M. A. Arnold, R. Delwel, P. J. Valk, J. Lohler, R. K. Slany, E. N. Olson, et al. Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C Blood, September 17, 2009; 114(12): 2476 - 2488. [Abstract] [Full Text] [PDF] J.-Y. Ahn, K. Seo, O. Weinberg, S. D. Boyd, and D. A. Arber A Comparison of Two Methods for Screening CEBPA Mutations in Patients with Acute Myeloid Leukemia J. Mol. Diagn., July 1, 2009; 11(4): 319 - 323. [Abstract] [Full Text] [PDF] A. Schuler, M. Schwieger, A. Engelmann, K. Weber, S. Horn, U. Muller, M. A. Arnold, E. N. Olson, and C. Stocking The MADS transcription factor Mef2c is a pivotal modulator of myeloid cell fate Blood, May 1, 2008; 111(9): 4532 - 4541. [Abstract] [Full Text] [PDF] M. Geletu, M. Y. Balkhi, A. A. Peer Zada, M. Christopeit, J. A. Pulikkan, A. K. Trivedi, D. G. Tenen, and G. Behre Target proteins of C/EBP{alpha}p30 in AML: C/EBP{alpha}p30 enhances sumoylation of C/EBP{alpha}p42 via up-regulation of Ubc9 Blood, November 1, 2007; 110(9): 3301 - 3309. [Abstract] [Full Text] [PDF] K. Y. Chung, G. Morrone, J. J. Schuringa, M. Plasilova, J.-H. Shieh, Y. Zhang, P. Zhou, and M. A.S. 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Serve AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations Blood, July 1, 2005; 106(1): 265 - 273. [Abstract] [Full Text] [PDF] P. F. Johnson Molecular stop signs: regulation of cell-cycle arrest by C/EBP transcription factors J. Cell Sci., June 15, 2005; 118(12): 2545 - 2555. [Abstract] [Full Text] [PDF] M. L. Smith, J. D. Cavenagh, T. A. Lister, and J. Fitzgibbon Mutation of CEBPA in Familial Acute Myeloid Leukemia N. Engl. J. Med., December 2, 2004; 351(23): 2403 - 2407. [Abstract] [Full Text] [PDF]

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