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Blood, 15 August 2006, Vol. 108, No. 4, pp. 1353-1362. Prepublished online as a Blood First Edition Paper on May 2, 2006; DOI 10.1182/blood-2006-01-011833. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-01-011833v1 108/4/1353    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 Ferrari-Amorotti, G. Articles by Calabretta, B. Search for Related Content PubMed PubMed Citation Articles by Ferrari-Amorotti, G. Articles by Calabretta, B. Related Collections Neoplasia Oncogenes and Tumor Suppressors Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Leukemogenesis induced by wild-type and STI571-resistant BCR/ABL is potently suppressed by C/EBP Giovanna Ferrari-Amorotti, Karen Keeshan, Michela Zattoni, Clara Guerzoni, Giorgio Iotti, Sara Cattelani, Nick J. Donato, and Bruno Calabretta From the Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson Medical College, Philadelphia, PA; the Department of Pathology, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia; and the Department of Bioimmunotherapy, University of Texas, M. D. Anderson Cancer Center, Houston. Chronic phase–to–blast crisis transition in chronic myelogenous leukemia (CML) is associated with differentiation arrest and down-regulation of C/EBP, a transcription factor essential for granulocyte differentiation. Patients with CML in blast crisis (CML-BC) became rapidly resistant to therapy with the breakpoint cluster region–Abelson murine leukemia (BCR/ABL) kinase inhibitor imatinib (STI571) because of mutations in the kinase domain that interfere with drug binding. We show here that the restoration of C/EBP activity in STI571-sensitive or -resistant 32D-BCR/ABL cells induced granulocyte differentiation, inhibited proliferation in vitro and in mice, and suppressed leukemogenesis. Moreover, activation of C/EBP eradicated leukemia in 4 of 10 and in 6 of 7 mice injected with STI571-sensitive or -resistant 32D-BCR/ABL cells, respectively. Differentiation induction and proliferation inhibition were required for optimal suppression of leukemogenesis, as indicated by the effects of p42 C/EBP, which were more potent than those of K298E C/EBP, a mutant defective in DNA binding and transcription activation that failed to induce granulocyte differentiation. Activation of C/EBP in blast cells from 4 patients with CML-BC, including one resistant to STI571 and BMS-354825 and carrying the T315I Abl kinase domain mutation, also induced granulocyte differentiation. Thus, these data indicate that C/EBP has potent antileukemia effects even in cells resistant to ATP-binding competitive tyrosine kinase inhibitors, and they portend the development of anti-leukemia therapies that rely on C/EBP activation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: W. W. Zhang, J. E. Cortes, H. Yao, L. Zhang, N. G. Reddy, E. Jabbour, H. M. Kantarjian, and D. Jones Predictors of Primary Imatinib Resistance in Chronic Myelogenous Leukemia Are Distinct From Those in Secondary Imatinib Resistance J. Clin. Oncol., August 1, 2009; 27(22): 3642 - 3649. [Abstract] [Full Text] [PDF] S. Koschmieder, B. Halmos, E. Levantini, and D. G. Tenen Dysregulation of the C/EBP{alpha} Differentiation Pathway in Human Cancer J. Clin. Oncol., February 1, 2009; 27(4): 619 - 628. [Abstract] [Full Text] [PDF] A. R. Soliera, M. R. Lidonnici, G. Ferrari-Amorotti, M. Prisco, Y. Zhang, R. V. Martinez, N. J. Donato, and B. Calabretta Transcriptional repression of c-Myb and GATA-2 is involved in the biologic effects of C/EBP{alpha} in p210BCR/ABL-expressing cells Blood, September 1, 2008; 112(5): 1942 - 1950. [Abstract] [Full Text] [PDF] H. Schepers, A. T. J. Wierenga, D. van Gosliga, B. J. L. Eggen, E. Vellenga, and J. J. Schuringa Reintroduction of C/EBP{alpha} in leukemic CD34+ stem/progenitor cells impairs self-renewal and partially restores myelopoiesis Blood, August 15, 2007; 110(4): 1317 - 1325. [Abstract] [Full Text] [PDF] J. S. Chang, R. Santhanam, R. Trotta, P. Neviani, A. M. Eiring, E. Briercheck, M. Ronchetti, D. C. Roy, B. Calabretta, M. A. Caligiuri, et al. High levels of the BCR/ABL oncoprotein are required for the MAPK-hnRNP-E2 dependent suppression of C/EBP{alpha}-driven myeloid differentiation Blood, August 1, 2007; 110(3): 994 - 1003. [Abstract] [Full Text] [PDF]

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