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Blood, 1 July 2007, Vol. 110, No. 1, pp. 360-369. Prepublished online as a Blood First Edition Paper on March 27, 2007; DOI 10.1182/blood-2006-12-065615. This Article Full Text (PDF) All Versions of this Article: blood-2006-12-065615v1 110/1/360    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 Dong, S. Articles by Chen, J. Search for Related Content PubMed PubMed Citation Articles by Dong, S. Articles by Chen, J. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 28, 2006 Accepted March 22, 2007 14-3-3 integrates pro-survival signals mediated by the AKT and MAPK pathways in ZNF198-FGFR1 transformed hematopoietic cells Shaozhong Dong, Sumin Kang, Tinglei Gu, Sean Kardar, Haian Fu, Sagar Lonial, Hanna Jean Khoury, Fadlo Khuri, and Jing Chen* Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, United States Cell Signaling Technologies Inc., Beverly, MA, United States Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, United States * Corresponding author; email: jchen{at}emory.edu. Human 8p11 stem cell leukemia/lymphoma syndrome usually presents as a myeloproliferative disorder (MPD) that evolves to acute myeloid leukemia and/or lymphoma. The syndrome associated with t(8;13)(p11;q12) results in expression of the ZNF198-FGFR1 fusion tyrosine kinase that plays a pathogenic role in hematopoietic transformation. We found that ZNF198-FGFR1 activated both AKT and MAPK pro-survival signaling pathways, resulting in elevated phosphorylation of FOXO3a at T32 and BAD at S112, respectively. These phosphorylated residues subsequently sequestered the pro-apoptotic FOXO3a and BAD to 14-3-3 to prevent apoptosis. We utilized a peptide-based 14-3-3 competitive antagonist, R18 to disrupt 14-3-3/ligand association. Expression of R18 effectively induced apoptosis in hematopoietic Ba/F3 cells transformed by ZNF198-FGFR1 compared with control cells. Moreover, purified recombinant TAT-conjugated R18 proteins effectively transduced into human leukemia cells, and induced significant apoptosis in KG-1a cells expressing FGFR1OP2-FGFR1 fusion tyrosine kinase, but not in control HL-60 and Jurkat-T cells. Surprisingly, R18 was only able to dissociate FOXO3a, but not BAD as previously proposed, from 14-3-3 binding, and induced apoptosis partially through liberation and reactivation of FOXO3a. Our findings suggest that 14-3-3 integrates pro-survival signals in FGFR1 fusion transformed hematopoietic cells. Disrupting 14-3-3/ligand association may represent an effective therapeutic strategy to treat 8p11 stem cell MPD. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Rahmani, A. Anderson, J. R. Habibi, T. R. Crabtree, M. Mayo, H. Harada, A. Ferreira-Gonzalez, P. Dent, and S. Grant The BH3-only protein Bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK1/2 pathways Blood, November 12, 2009; 114(20): 4507 - 4516. [Abstract] [Full Text] [PDF] B. S. Ajjappala, Y.-S. Kim, M.-S. Kim, M.-Y. Lee, K.-Y. Lee, H.-Y. Ki, D.-H. Cha, and K.-H. Baek 14-3-3{gamma} Is Stimulated by IL-3 and Promotes Cell Proliferation J. Immunol., January 15, 2009; 182(2): 1050 - 1060. [Abstract] [Full Text] [PDF] C. Weidinger, K. Krause, A. Klagge, S. Karger, and D. Fuhrer Forkhead box-O transcription factor: critical conductors of cancer's fate Endocr. Relat. Cancer, December 1, 2008; 15(4): 917 - 929. [Abstract] [Full Text] [PDF]

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