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SPECIAL FOCUS
Reduced Retinoic Acid-Sensitivities of Nuclear Receptor Corepressor
Binding to PML- and PLZF-RAR Underlie Molecular Pathogenesis and
Treatment of Acute Promyelocytic Leukemia
Fabien Guidez,
Sarah Ivins,
Jun Zhu,
Mats Söderström,
Samuel Waxman, and
Arthur Zelent
From the Leukaemia Research Fund Centre at the Institute of Cancer
Research, Chester Beatty Laboratories, London, UK; the Department of
Cell Biology, Faculty of Health Sciences, University of
Linköping, Linköping, Sweden; and the Department of
Medicine, Mount Sinai School of Medicine, New York, NY.
Typical acute promyelocytic leukemia (APL) is associated with
expression of the PML-RAR fusion protein and responsiveness to
treatment with all-trans retinoic acid (ATRA). A rare, but recurrent, APL has been described that does not respond to ATRA treatment and is associated with a variant chromosomal translocation and expression of the PLZF-RAR fusion protein. Both PML- and PLZF-RAR possess identical RAR sequences and inhibit ATRA-induced gene transcription as well as cell differentiation. We now show that
the above-mentioned oncogenic fusion proteins interact with the nuclear
receptor corepressor N-CoR and, in comparison with the wild-type RAR
protein, their interactions display reduced sensitivities to ATRA.
Although pharmacologic concentration of ATRA could still induce
dissociation of N-CoR from PML-RAR, it had a very little effect on
its association with the PLZF-RAR fusion protein. This
ATRA-insensitive interaction between N-CoR and PLZF-RAR was mediated
by the N-terminal PLZF moiety of the chimera. It appears that
N-CoR/histone deacetylase corepressor complex interacts directly in an
ATRA-insensitive manner with the BTB/POZ-domain of the wild-type PLZF
protein and is required, at least in part, for its function as a
transcriptional repressor. As the above-noted results predict, histone
deacetylase inhibitors antagonize oncogenic activities of the
PML-RAR fusion protein and partially relieve transcriptional
repression by PLZF as well as inhibitory effect of PLZF-RAR on ATRA
response. Taken together, our results demonstrate involvement of
nuclear receptor corepressor/histone deacetylase complex in the
molecular pathogenesis of APL and provide an explanation for
differential sensitivities of PML- and PLZF-RAR-associated leukemias to ATRA.
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2634-2642
© 1998 by The American Society of Hematology.
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