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Blood, 1 December 2001, Vol. 98, No. 12, pp. 3290-3300
HEMATOPOIESIS
The acute promyelocytic leukemia-associated protein,
promyelocytic leukemia zinc finger, regulates 1,25-dihydroxyvitamin
D3-induced monocytic differentiation of U937 cells through
a physical interaction with vitamin D3
receptor
Jeremy O. Ward,
Melanie J. McConnell,
Graeme W. Carlile,
Pier Paolo Pandolfi,
Jonathan D. Licht, and
Leonard P. Freedman
From the Programs of Cell Biology and Human
Genetics, Memorial Sloan-Kettering Cancer Center and
Sloan-Kettering Division, Joan and Sanford I. Weill Graduate School of
Medical Sciences of Cornell University; and the Department of Medicine
Biochemistry and Molecular Biology, Derald H. Ruttenberg Cancer Center,
Mount Sinai School of Medicine, New York, NY.
Monocyte differentiation induced by 1,25-dihydroxyvitamin
D3 (1,25(OH)2D3) is interrupted
during the course of acute promyelocytic leukemia (APL). One form of
APL is associated with the translocation t(11;17), which joins the
promyelocytic leukemia zinc finger (PLZF) and retinoic acid receptor
 (RAR) genes. Because PLZF is coexpressed in the myeloid lineage
with the vitamin D3 receptor (VDR), the interplay between
PLZF and VDR was examined. It was found that PLZF interacts directly
with VDR. This occurred at least partly through contacts in the
DNA-binding domain of VDR and the broad complex, tram-trak,
bric-a-brac/pox virus zinc finger (BTB/POZ) domain of PLZF. Moreover,
PLZF altered the mobility of VDR derived from nuclear extracts when
bound to its cognate binding site, forming a slowly migrating
DNA-protein complex. Overexpression of PLZF in a monocytic cell line
abrogated 1,25(OH)2D3 activation from both a
minimal VDR responsive reporter and the promoter of p21WAF1/CIP1, a target gene of VDR. Deletion of
the BTB/POZ domain significantly relieved PLZF-mediated repression of
1,25(OH)2D3-dependent activation. In addition,
stable, inducible expression of PLZF in U937 cells inhibited the
ability of 1,25(OH)2D3 to induce surface
expression of the monocytic marker CD14 and morphologic changes
associated with differentiation. These results suggest that PLZF may
play an important role in regulating the process by which
1,25(OH)2D3 induces monocytic differentiation
in hematopoietic cells.
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