PML-Retinoic Acid Receptor α Inhibits PML IV Enhancement of PU.1-Induced C/EBPε Expression in Myeloid Differentiation

Abstract

PML and PU.1 play important roles in myeloid differentiation. PML-deficient mice have an impaired capacity for terminal maturation of their myeloid precursor cells. This finding has been explained, at least in part, by the lack of PML action to modulate retinoic acid-differentiating activities. In this study, we found that C/EBPε expression is reduced in PML-deficient mice. We showed that PU.1 directly activates the transcription of the C/EBPε gene that is essential for granulocytic differentiation. The type IV isoform of PML interacted with PU.1, promoted its association with p300, and then enhanced PU.1-induced transcription and granulocytic differentiation. In contrast to PML IV, the leukemia-associated PML-retinoic acid receptor α fusion protein dissociated the PU.1/PML IV/p300 complex and inhibited PU.1-induced transcription. These results suggest a novel pathogenic mechanism of the PML-retinoic acid receptor α fusion protein in acute promyelocytic leukemia.

SUPPLEMENTAL MATERIAL

We thank Francoise Moreau-Gachelin (INSERM, France), Zu Chen (Shanghai Institute of Hematology, People's Republic of China), Akira Kakizuka (Kyoto University, Japan), and Pierre Chambon (INSERM, France) for kindly providing the cDNAs for PU.1, PLZF-RARA, PML-RARA, and RAR and retinoid X receptor, respectively. We also thank Kimiko Shimizu and Kazutsune Yamagata for supervision of the ChIP assay and Chikako Hatanaka and Noriko Aikawa for technical assistance.

This work was supported in part by a grant-in-aid from the Japanese Ministry of Education, Culture, Sports, and Science and by a grant from the Leukemia Study Group of the Ministry of Health, Labor, and Welfare.