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Mol Cell Biol, July 1998, p. 4301-4314, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

CCAAT/Enhancer Binding Protein alpha  Is a Regulatory Switch Sufficient for Induction of Granulocytic Development from Bipotential Myeloid Progenitors

Hanna S. Radomska,1 Claudia S. Huettner,1 Pu Zhang,1 Tao Cheng,2 David T. Scadden,2 and Daniel G. Tenen1 *

Hematology/Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School,1 and MGH Cancer Center and AIDS Research Center, Massachusetts General Hospital and Harvard Medical School,2 Boston, Massachusetts

Received 11 November 1997/Returned for modification 4 January 1998/Accepted 24 March 1998

The transcription factor CCAAT/enhancer binding protein alpha  (C/EBPalpha ) regulates a number of myeloid cell-specific genes. To delineate the role of C/EBPalpha in human granulopoiesis, we studied its expression and function in human primary cells and bipotential (granulocytic/monocytic) myeloid cell lines. We show that the expression of C/EBPalpha initiates with the commitment of multipotential precursors to the myeloid lineage, is specifically upregulated during granulocytic differentiation, and is rapidly downregulated during the alternative monocytic pathway. Conditional expression of C/EBPalpha alone in stably transfected bipotential cells triggers neutrophilic differentiation, concomitant with upregulation of the granulocyte-specific granulocyte colony-stimulating factor receptor and secondary granule protein genes. Moreover, induced expression of C/EBPalpha in bipotential precursors blocks their monocytic differentiation program. These results indicate that C/EBPalpha serves as a myeloid differentiation switch acting on bipotential precursors and directing them to mature to granulocytes.

* Corresponding author. Mailing address: Harvard Institutes of Medicine, Room 954, 77 Ave. Louis Pasteur, Boston, MA 02115. Phone: (617) 667-5561. Fax: (617) 667-3299. E-mail: dtenen{at}bidmc.harvard.edu.

Mol Cell Biol, July 1998, p. 4301-4314, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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  • Truong, B.-T. H., Lee, Y.-J., Lodie, T. A., Park, D. J., Perrotti, D., Watanabe, N., Koeffler, H. P., Nakajima, H., Tenen, D. G., Kogan, S. C. (2003). CCAAT/Enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia. Blood 101: 1141-1148 [Abstract] [Full Text]  
  • Rangatia, J., Vangala, R. K., Treiber, N., Zhang, P., Radomska, H., Tenen, D. G., Hiddemann, W., Behre, G. (2002). Downregulation of c-Jun Expression by Transcription Factor C/EBP{alpha} Is Critical for Granulocytic Lineage Commitment. Mol. Cell. Biol. 22: 8681-8694 [Abstract] [Full Text]  
  • Welm, A. L., Timchenko, N. A., Ono, Y., Sorimachi, H., Radomska, H. S., Tenen, D. G., Lekstrom-Himes, J., Darlington, G. J. (2002). C/EBPalpha Is Required for Proteolytic Cleavage of Cyclin A by Calpain 3 in Myeloid Precursor Cells. J. Biol. Chem. 277: 33848-33856 [Abstract] [Full Text]  
  • Tsujimura, H., Nagamura-Inoue, T., Tamura, T., Ozato, K. (2002). IFN Consensus Sequence Binding Protein/IFN Regulatory Factor-8 Guides Bone Marrow Progenitor Cells Toward the Macrophage Lineage. J. Immunol. 169: 1261-1269 [Abstract] [Full Text]  
  • Behre, G., Singh, S. M., Liu, H., Bortolin, L. T., Christopeit, M., Radomska, H. S., Rangatia, J., Hiddemann, W., Friedman, A. D., Tenen, D. G. (2002). Ras Signaling Enhances the Activity of C/EBPalpha to Induce Granulocytic Differentiation by Phosphorylation of Serine 248. J. Biol. Chem. 277: 26293-26299 [Abstract] [Full Text]  
  • Reddy, V. A., Iwama, A., Iotzova, G., Schulz, M., Elsasser, A., Vangala, R. K., Tenen, D. G., Hiddemann, W., Behre, G. (2002). Granulocyte inducer C/EBPalpha inactivates the myeloid master regulator PU.1: possible role in lineage commitment decisions. Blood 100: 483-490 [Abstract] [Full Text]  
  • Parkin, S. E., Baer, M., Copeland, T. D., Schwartz, R. C., Johnson, P. F. (2002). Regulation of CCAAT/Enhancer-binding Protein (C/EBP) Activator Proteins by Heterodimerization with C/EBPgamma (Ig/EBP). J. Biol. Chem. 277: 23563-23572 [Abstract] [Full Text]  
  • Zhang, P., Nelson, E., Radomska, H. S., Iwasaki-Arai, J., Akashi, K., Friedman, A. D., Tenen, D. G. (2002). Induction of granulocytic differentiation by 2 pathways. Blood 99: 4406-4412 [Abstract] [Full Text]  
  • Kallies, A., Rosenbauer, F., Scheller, M., Knobeloch, K.-P., Horak, I. (2002). Accumulation of c-Cbl and rapid termination of colony-stimulating factor 1 receptor signaling in interferon consensus sequence binding protein-deficient bone marrow-derived macrophages. Blood 99: 3213-3219 [Abstract] [Full Text]  
  • Wang, Q.-f., Friedman, A. D. (2002). CCAAT/enhancer-binding proteins are required for granulopoiesis independent of their induction of the granulocyte colony-stimulating factor receptor. Blood 99: 2776-2785 [Abstract] [Full Text]  
  • Iervolino, A., Santilli, G., Trotta, R., Guerzoni, C., Cesi, V., Bergamaschi, A., Gambacorti-Passerini, C., Calabretta, B., Perrotti, D. (2002). hnRNP A1 Nucleocytoplasmic Shuttling Activity Is Required for Normal Myelopoiesis and BCR/ABL Leukemogenesis. Mol. Cell. Biol. 22: 2255-2266 [Abstract] [Full Text]  
  • Kim, J., Feldman, R. A. (2002). Activated Fes Protein Tyrosine Kinase Induces Terminal Macrophage Differentiation of Myeloid Progenitors (U937 Cells) and Activation of the Transcription Factor PU.1. Mol. Cell. Biol. 22: 1903-1918 [Abstract] [Full Text]  
  • Jones, L. C., Lin, M.-L., Chen, S.-S., Krug, U., Hofmann, W.-K., Lee, S., Lee, Y.-H., Koeffler, H. P. (2002). Expression of C/EBPbeta from the C/ebpalpha gene locus is sufficient for normal hematopoiesis in vivo. Blood 99: 2032-2036 [Abstract] [Full Text]  
  • Iwama, A., Osawa, M., Hirasawa, R., Uchiyama, N., Kaneko, S., Onodera, M., Shibuya, K., Shibuya, A., Vinson, C., Tenen, D. G., Nakauchi, H. (2002). Reciprocal Roles for CCAAT/Enhancer Binding Protein (C/EBP) and PU.1 Transcription Factors in Langerhans Cell Commitment. JEM 195: 547-558 [Abstract] [Full Text]  
  • Gombart, A. F., Hofmann, W.-K., Kawano, S., Takeuchi, S., Krug, U., Kwok, S. H., Larsen, R. J., Asou, H., Miller, C. W., Hoelzer, D., Koeffler, H. P. (2002). Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. Blood 99: 1332-1340 [Abstract] [Full Text]  
  • Halmos, B., Huettner, C. S., Kocher, O., Ferenczi, K., Karp, D. D., Tenen, D. G. (2002). Down-Regulation and Antiproliferative Role of C/EBP{alpha} in Lung Cancer. Cancer Res. 62: 528-534 [Abstract] [Full Text]  
  • Pedersen, T. A., Kowenz-Leutz, E., Leutz, A., Nerlov, C. (2001). Cooperation between C/EBPalpha TBP/TFIIB and SWI/SNF recruiting domains is required for adipocyte differentiation. Genes Dev. 15: 3208-3216 [Abstract] [Full Text]  
  • Collins, S. J., Ulmer, J., Purton, L. E., Darlington, G. (2001). Multipotent hematopoietic cell lines derived from C/EBP{alpha}({-}/{-}) knockout mice display granulocyte macrophage-colony-stimulating factor, granulocyte- colony-stimulating factor, and retinoic acid-induced granulocytic differentiation. Blood 98: 2382-2388 [Abstract] [Full Text]  
  • Schaufele, F., Enwright, J. F. III, Wang, X., Teoh, C., Srihari, R., Erickson, R., MacDougald, O. A., Day, R. N. (2001). CCAAT/Enhancer Binding Protein {alpha} Assembles Essential Cooperating Factors in Common Subnuclear Domains. Mol. Endocrinol. 15: 1665-1676 [Abstract] [Full Text]  
  • Burel, S. A., Harakawa, N., Zhou, L., Pabst, T., Tenen, D. G., Zhang, D.-E. (2001). Dichotomy of AML1-ETO Functions: Growth Arrest versus Block of Differentiation. Mol. Cell. Biol. 21: 5577-5590 [Abstract] [Full Text]  
  • Nakajima, H., Ihle, J. N. (2001). Granulocyte colony-stimulating factor regulates myeloid differentiation through CCAAT/enhancer-binding protein {epsilon}. Blood 98: 897-905 [Abstract] [Full Text]  
  • Johansen, L. M., Iwama, A., Lodie, T. A., Sasaki, K., Felsher, D. W., Golub, T. R., Tenen, D. G. (2001). c-Myc Is a Critical Target for C/EBP{alpha} in Granulopoiesis. Mol. Cell. Biol. 21: 3789-3806 [Abstract] [Full Text]  


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