This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow An author's correction has been published
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Phan, V. T.
Right arrow Articles by Kogan, S. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Phan, V. T.
Right arrow Articles by Kogan, S. C.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, July 2003, p. 4573-4585, Vol. 23, No. 13
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.13.4573-4585.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Cooperation of Cytokine Signaling with Chimeric Transcription Factors in Leukemogenesis: PML-Retinoic Acid Receptor Alpha Blocks Growth Factor-Mediated Differentiation

Vernon T. Phan,1 David B. Shultz,1,{dagger} Bao-Tran H. Truong,1,{ddagger} Timothy J. Blake,2 Anna L. Brown,2 Thomas J. Gonda,2,§ Michelle M. Le Beau,3 and Scott C. Kogan1*

Department of Laboratory Medicine and Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California,1 Hanson Institute and Division of Human Immunology, Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia,2 Section of Hematology/Oncology, University of Chicago, Chicago, Illinois3

Received 13 September 2002/ Returned for modification 8 November 2002/ Accepted 19 March 2003

We utilized a mouse model of acute promyelocytic leukemia (APL) to investigate how aberrant activation of cytokine signaling pathways interacts with chimeric transcription factors to generate acute myeloid leukemia. Expression in mice of the APL-associated fusion, PML-RARA, initially has only modest effects on myelopoiesis. Whereas treatment of control animals with interleukin-3 (IL-3) resulted in expanded myelopoiesis without a block in differentiation, PML-RARA abrogated differentiation that normally characterizes the response to IL-3. Retroviral transduction of bone marrow with an IL-3-expressing retrovirus revealed that IL-3 and promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR{alpha}) combined to generate a lethal leukemia-like syndrome in <21 days. We also observed that a constitutively activated mutant IL-3 receptor, ßcV449E, cooperated with PML-RAR{alpha} in leukemogenesis, whereas a different activated mutant, ßcI374N, did not. Analysis of additional mutations introduced into ßcV449E showed that, although tyrosine phosphorylation of ßc is necessary for cooperation, the Src homology 2 domain-containing transforming protein binding site is dispensable. Our results indicate that chimeric transcription factors can block the differentiative effects of growth factors. This combination can be potently leukemogenic, but the particular manner in which these types of mutations interact determines the ability of such combinations to generate acute myeloid leukemia.

* Corresponding author. Mailing address: UCSF Comprehensive Cancer Center, 2340 Sutter St., Rm. N-361, Box 0128, San Francisco, CA 94143-0128. Phone: (415) 514-1590. Fax: (415) 502-3179. E-mail: skogan{at}cc.ucsf.edu.

{dagger} Present address: School of Medicine, Case Western Reserve University, Cleveland, Ohio.

{ddagger} Present address: Genentech, Inc., South San Francisco, Calif.

§ Present address: Bionomics, Ltd., Adelaide, South Australia, Australia.

Molecular and Cellular Biology, July 2003, p. 4573-4585, Vol. 23, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.13.4573-4585.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»