4.7 Article

Opposing effects of PML and PML/RARα on STAT3 activity

Journal

BLOOD
Volume 101, Issue 9, Pages 3668-3673

Publisher

AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2002-08-2474

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Promyelocytic leukemia protein PML acts as a tumor suppressor, whereas its chimeric mutant promyelocytic leukemia/retinoic acid receptoralpha (PML/RARalpha) 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/RARalpha might affect signal transducer and activator of transcription 3 (STAT3) activity, which plays a crucial role in granulocyte colony-stimulating factor (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/RARalpha did not interact with STAT3, it dissociated PML from STAT3 and restored its activity suppressed by PML. To assess the biologic significance of these findings, we introduced PML and PML/RARalpha, into interleukin-3 (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/RARalpha affected IL-3-dependent growth of these clones. By contrast, gp130-mediated growth was abrogated by PML, whereas it was enhanced. by PML/RARalpha. These results reveal new functions of PML and PML/RARalpha, and suggest that dysregulated STAT3 activity by PML/RARalpha may participate in the pathogenesis of APL. (C) 2003 by The American Society of Hematology.

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