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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, Bao-Tran H. Truong,^1, Timothy J. Blake,² Anna L. Brown,² Thomas J. Gonda,^2, Michelle M. Le Beau,³ and Scott C. Kogan^1*

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) combined to generate a lethal leukemia-like syndrome in <21 days. We also observed that a constitutively activated mutant IL-3 receptor, ß_cV449E, cooperated with PML-RAR in leukemogenesis, whereas a different activated mutant, ß_cI374N, did not. Analysis of additional mutations introduced into ß_cV449E showed that, although tyrosine phosphorylation of ß_c 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.

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

Present address: Genentech, Inc., South San Francisco, Calif.

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