The promyelocytic leukemia zinc finger protein affects myeloid cell growth, differentiation, and apoptosis.
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.
Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, New York, New York, USA.
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R
Shaknovich
P L
PL
Yeyati
S
S
Ivins
A
A
Melnick
C
C
Lempert
S
S
Waxman
A
A
Zelent
J D
JD
Licht
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000502:physiology*; D016193:G1 Phase; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006131:Growth Inhibitors / Q000096:biosynthesis; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011994:Recombinant Proteins / Q000096:biosynthesis; D016192:Resting Phase, Cell Cycle; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology*; D014162:Transfection; D016335:Zinc Fingers
D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D007377:Interleukin-3; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011994:Recombinant Proteins; D014157:Transcription Factors; C513267:Zbtb16 protein, mouse; D016179:Granulocyte Colony-Stimulating Factor; C092037:ZBTB16 protein, human; D016178:Granulocyte-Macrophage Colony-Stimulating Factor