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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 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 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 Schwieger, M. Articles by Stocking, C. Search for Related Content PubMed PubMed Citation Articles by Schwieger, M. Articles by Stocking, C. Related Collections Hematopoiesis and Stem Cells Neoplasia Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA 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, Jürgen Löhler, Meike Fischer, Uwe Herwig, Daniel G. Tenen, and Carol Stocking From the Molecular Pathology Group, Heinrich-Pette-Institut für Experimentelle Immunologie und Virologie, Hamburg, Germany; Albertinen-Krankenhaus, Hamburg, Germany; and Harvard Institutes of Medicine, Boston, MA. 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 an 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 coexpression of both myeloid and erythroid markers in the immature transformed cells. Surprisingly, mut10 did not block myelocytic differentiation in murine progenitors but did alter their differentiation kinetics and clonogenicity. Experiments were performed to confirm 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. (Blood. 2004;103:2744-2752) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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. Moore Enforced Expression of NUP98-HOXA9 in Human CD34+ Cells Enhances Stem Cell Proliferation Cancer Res., December 15, 2006; 66(24): 11781 - 11791. [Abstract] [Full Text] [PDF] H. S. Radomska, D. S. Basseres, R. Zheng, P. Zhang, T. Dayaram, Y. Yamamoto, D. W. Sternberg, N. Lokker, N. A. Giese, S. K. Bohlander, et al. Block of C/EBP{alpha} function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations J. Exp. Med., February 21, 2006; 203(2): 371 - 381. [Abstract] [Full Text] [PDF] A. G. Muntean and J. D. Crispino Differential requirements for the activation domain and FOG-interaction surface of GATA-1 in megakaryocyte gene expression and development Blood, August 15, 2005; 106(4): 1223 - 1231. [Abstract] [Full Text] [PDF] C. Choudhary, J. Schwable, C. Brandts, L. Tickenbrock, B. Sargin, T. Kindler, T. Fischer, W. E. Berdel, C. Muller-Tidow, and H. 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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