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Original Article

^a From the Department of Human Genetics and the Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, New York, New York 10021
Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021.212-717-3374212-639-6168

p-pandolfi{at}ski.mskcc.org

The promyelocytic leukemia protein (PML) gene of acute promyelocytic leukemia (APL) encodes a cell growth and tumor suppressor essential for multiple apoptotic signals. Daxx was identified as a molecule important for the cytoplasmic transduction of the Fas proapoptotic stimulus. Here, we show that upon mitogenic activation of mature splenic lymphocytes, Daxx is dramatically upregulated and accumulates in the PML nuclear body (NB) where PML and Daxx physically interact. In the absence of PML, Daxx acquires a dispersed nuclear pattern, and activation-induced cell death of splenocytes is profoundly impaired. PML inactivation results in the complete abrogation of the Daxx proapoptotic ability. In APL cells, Daxx is delocalized from the NB. Upon retinoic acid treatment, which induces disease remission in APL, Daxx relocalizes to the PML NBs. These results indicate that PML and Daxx cooperate in a novel NB-dependent pathway for apoptosis and shed new light in the role of PML in tumor suppression.

Key Words: apoptosis • PML • Daxx • nuclear body • acute promyelocytic leukemia

Abbreviations used in this paper: APL, acute promyelocytic leukemia; ASK1, apoptosis signal–regulating kinase 1; BFP, blue fluorescent protein; DAPI, 4,6-diamino-2-phenylindole; FADD, Fas-associated death domain protein; GFP, green fluorescent protein; Hsp90, heat shock protein 90; JNK, c-Jun NH₂-terminal kinase; NB, nuclear body; PML, promyelocytic leukemia protein; RA, retinoic acid; RAR and RXR, RA receptor and RA receptor X, respectively; SD, synthetic dropout; TUNEL, terminal deoxynucleotidyl–mediated dUTP nick end labeling.

© 2000 The Rockefeller University Press

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