|
|
 Previous Article | Table of Contents | Next Article 
Blood, 1 November 2000, Vol. 96, No. 9, pp. 3200-3208
NEOPLASIA
Altered ligand binding and transcriptional regulation by
mutations in the PML/RAR ligand-binding domain arising in retinoic
acid-resistant patients with acute promyelocytic leukemia
Sylvie Côté,
Dacheng Zhou,
Andrea Bianchini,
Clara Nervi,
Robert E. Gallagher, and
Wilson
H. Miller Jr
From the Lady Davis Institute for Medical Research, Sir
Mortimer B. Davis Jewish General Hospital, and the McGill University
Department of Oncology and Medicine, Montreal, Quebec, Canada;
Montefiore Medical Center and Albert Einstein Cancer Center, Bronx, NY;
and Dipartimento di Istologia ed Embriologia Medica, Università
di Roma "La Sapienza," Rome, Italy.
Acute promyelocytic leukemia (APL) is characterized by a specific
translocation, t(15;17), that fuses the promyelocytic leukemia (PML) gene with the RA receptor RAR .
Pharmacologic doses of retinoic acid (RA) induce differentiation in
human APL cells and complete clinical remissions. Unfortunately, APL
cells develop resistance to RA in vitro and in vivo. Recently,
mutations in PML/RAR have been described in APL cells
from patients clinically resistant to RA therapy. The mutations cluster
in 2 regions that are involved in forming the binding pocket for RA.
These mutant PML/RAR proteins have been expressed in vitro,
which shows that they cause a diversity of alterations in binding to
ligand and to nuclear coregulators of transcription, leading to varying
degrees of inhibition of retinoid-induced transcription. This contrasts
with the nearly complete dominant negative activity of mutations in
PML/RAR previously characterized in cell lines developing RA
resistance in vitro. Current data from this study provide additional
insight into the molecular mechanisms of resistance to RA and suggest
that alterations in the ability of mutants to interact with
coregulators can be determinant in the molecular mechanism of
resistance to RA. In particular, ligand-induced binding to the
coactivator ACTR correlated better with transcriptional
activation of RA response elements than the ligand-induced release of
the corepressor SMRT. The diversity of effects that are seen in
patient-derived mutations may help explain the partial success to date
of attempts to overcome this mechanism of resistance in patients by the
clinical use of histone deacetylase inhibitors.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
R. Quere, A. Baudet, B. Cassinat, G. Bertrand, J. Marti, L. Manchon, D. Piquemal, C. Chomienne, and T. Commes
Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity
Blood,
May 15, 2007;
109(10):
4450 - 4460.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Matsushita, P. P. Scaglioni, M. Bhaumik, E. M. Rego, L. F. Cai, S. M. Majid, H. Miyachi, A. Kakizuka, W. H. Miller Jr., and P. P. Pandolfi
In vivo analysis of the role of aberrant histone deacetylase recruitment and RAR{alpha} blockade in the pathogenesis of acute promyelocytic leukemia
J. Exp. Med.,
April 17, 2006;
203(4):
821 - 828.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Jyrkkarinne, B. Windshugel, J. Makinen, M. Ylisirnio, M. Perakyla, A. Poso, W. Sippl, and P. Honkakoski
Amino Acids Important for Ligand Specificity of the Human Constitutive Androstane Receptor
J. Biol. Chem.,
February 18, 2005;
280(7):
5960 - 5971.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Cote, S. McNamara, D. Brambilla, A. Bianchini, G. Rizzo, S. V. del Rincon, F. Grignani, C. Nervi, and W. H. Miller Jr
Expression of SMRT{beta} promotes ligand-induced activation of mutated and wild-type retinoid receptors
Blood,
December 15, 2004;
104(13):
4226 - 4235.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Gilbert, S. D. Gore, J. G. Herman, and M. A. Carducci
The Clinical Application of Targeting Cancer through Histone Acetylation and Hypomethylation
Clin. Cancer Res.,
July 15, 2004;
10(14):
4589 - 4596.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Davison, K. K. Mann, S. Waxman, and W. H. Miller Jr
JNK activation is a mediator of arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells
Blood,
May 1, 2004;
103(9):
3496 - 3502.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Cote, A. Rosenauer, A. Bianchini, K. Seiter, J. Vandewiele, C. Nervi, and W. H. Miller Jr
Response to histone deacetylase inhibition of novel PML/RARalpha mutants detected in retinoic acid-resistant APL cells
Blood,
September 18, 2002;
100(7):
2586 - 2596.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D.-C. Zhou, S. H. Kim, W. Ding, C. Schultz, R. P. Warrell Jr, and R. E. Gallagher
Frequent mutations in the ligand-binding domain of PML-RARalpha after multiple relapses of acute promyelocytic leukemia: analysis for functional relationship to response to all-trans retinoic acid and histone deacetylase inhibitors in vitro and in vivo
Blood,
February 15, 2002;
99(4):
1356 - 1363.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
