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Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-08-2474.
Submitted August 13, 2002
Accepted December 17, 2002
Opposing effects of PML and PML/RAR on STAT3 activity
Akira Kawasaki, Itaru Matsumura*, Yoshihisa Kataoka, Eri Takigawa, Koichi Nakajima, and Yuzuru Kanakura
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
Department of Immunology, Osaka City University Medical School, Osaka, Japan
* Corresponding author; email: matumura{at}bldon.med.osaka-u.ac.jp.
Promyelocytic leukemia protein PML acts as a tumor suppressor, while its chimeric mutant PML/RAR causes acute promyelocytic leukemia (APL). Because PML has been shown to form transcription-regulatory complexes with various molecules, we speculated that PML and/or PML/RAR might affect STAT3 activity, which plays a crucial role in G-CSF-induced growth and survival of myeloid cells. In luciferase assays, PML inhibited STAT3 activity in NIH3T3, 293T, HepG2 and 32D cells. PML formed a complex with STAT3 through B-box and COOH-terminal regions in vitro and in vivo, thereby inhibiting its DNA-binding activity. Although PML/RAR did not interact with STAT3, it dissociated PML from STAT3 and restored its activity suppressed by PML. To assess the biological significance of these findings, we introduced PML and PML/RAR into IL-3-dependent Ba/F3 cells expressing the chimeric receptor composed of extracellular domain of G-CSF-R and cytoplasmic domain of gp130, in which gp130-mediated growth is essentially dependent on STAT3 activity. Neither PML nor PML/RAR affected IL-3-dependent growth of these clones. By contrast, gp130-mediated growth was abrogated by PML, while it was enhanced by PML/RAR. These results revealed new functions of PML and PML/RAR, and proposed a possibility that dysregulated STAT3 activity by PML/RAR may participate in the pathogenesis of APL.
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