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

Abstract

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-RARα) combined to generate a lethal leukemia-like syndrome in <21 days. We also observed that a constitutively activated mutant IL-3 receptor, β_cV449E, cooperated with PML-RARα in leukemogenesis, whereas a different activated mutant, β_cI374N, did not. Analysis of additional mutations introduced into β_cV449E showed that, although tyrosine phosphorylation of β_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.

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

ACKNOWLEDGMENTS

We thank Warren Pear, Richard Van Etten, and Yosef Refaeli for their assistance with protocols for retroviral transduction of bone marrow; Sheila Bitts, Elizabeth M. Davis, and Bhumi Patel for assistance with cytogenetic analysis; Suzanne Cory for pMPZen-IL-3; H. Jeffrey Lawrence for critical comments on the manuscript and mentoring; and J. Michael Bishop, Kevin M. Shannon, and Daphne A. Haas-Kogan for helpful discussions and support.

S.C.K. is a recipient of a Burroughs Wellcome Fund Career Award and is the 32nd Edward Mallinckrodt Junior Scholar. Funding was also provided by grants CA75986 and CA95274 (S.C.K.) and CA84221 (S.C.K. and M.M.L.) from the National Institutes of Health and by the National Health and Medical Research Council of Australia (T.J.G.).