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Molecular and Cellular Biology, September 1998, p. 5533-5545, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Promyelocytic Leukemia Zinc Finger Protein Affects Myeloid Cell Growth, Differentiation, and Apoptosisdagger

Rita Shaknovich,1 Patricia L. Yeyati,1 Sarah Ivins,2 Ari Melnick,3 Cheryl Lempert,4 Samuel Waxman,3 Arthur Zelent,2 and Jonathan D. Licht1,3,*

Brookdale Center for Developmental and Molecular Biology1 and Departments of Medicine3 and Pediatrics,4 Mount Sinai School of Medicine, New York, New York, and The Leukemia Research Fund Center, Institute of Cancer Research, London, United Kingdom2

Received 20 October 1997/Returned for modification 24 November 1997/Accepted 26 May 1998

The promyelocytic leukemia zinc finger (PLZF) gene, which is disrupted in therapy-resistant, t(11;17)(q23;q21)-associated acute promyelocytic leukemia (APL), is expressed in immature hematopoietic cells and is down-regulated during differentiation. To determine the role of PLZF in myeloid development, we engineered expression of PLZF in murine 32Dcl3 cells. Expression of PLZF had a dramatic growth-suppressive effect accompanied by accumulation of cells in the G0/G1 compartment of the cell cycle and an increased incidence of apoptosis. PLZF-expressing pools also secreted a growth-inhibitory factor, which could explain the severe growth suppression of PLZF-expressing pools that occurred despite the fact that only half of the cells expressed high levels of PLZF. PLZF overexpression inhibited myeloid differentiation of 32Dcl3 cells in response to granulocyte and granulocyte-macrophage colony-stimulating factors. Furthermore, cells that expressed PLZF appeared immature as demonstrated by morphology, increased expression of Sca-1, and decreased expression of Gr-1. These findings suggest that PLZF is an important regulator of cell growth, death, and differentiation. Disruption of PLZF function associated with t(11;17) may be a critical event leading to APL.

* Corresponding author. Mailing address: Brookdale Center for Developmental and Molecular Biology and Department of Medicine, Box 1126, Mount Sinai School of Medicine, One Gustave L. Levy Pl., New York, NY 10029. Phone: (212) 241-9427. Fax: (212) 860-9279. E-mail: jlicht{at}smtplink.mssm.edu.

dagger Publication no. 249 from the Brookdale Center for Developmental and Molecular Biology.

Molecular and Cellular Biology, September 1998, p. 5533-5545, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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