|
|
Prepublished online as a Blood First Edition Paper on June 7, 2002; DOI 10.1182/blood-2002-02-0614.
Submitted February 25, 2002
Accepted May 15, 2002
Response to histone deacetylase inhibition of novel PML/RAR mutants detected in retinoic acid resistant APL cells
Sylvie Cote, Angelika Rosenauer, Andrea Bianchini, Karen Seiter, Jonathan Vandewiele, Clara Nervi, and Wilson H Miller*
Lady Davis Institute for Medical Research and McGill University Department of Oncology and Medicine, Sir Mortimer B Davis Jewish General Hospital, Montreal, PQ, Canada
Dipartimento di Istologia ed Embriologia Medica, Universita di Roma, Rome, Italy
Department of Medicine/Neoplastic Diseases, New York Medical College, Valhalla, NY, USA
* Corresponding author; email: wmiller{at}ldi.jgh.mcgill.ca.
Resistance to all-trans retinoic acid (RA) remains a clinical problem in the treatment of acute promyelocytic leukemia (APL) and provides a model for the development of novel therapies. Molecular alterations in the ligand-binding domain (LBD) of the PML/RAR fusion gene that characterizes APL constitute one mechanism by which leukemic cells may acquire resistance to RA. We identified missense mutations in the RAR portion of PML/RAR from an additional RA-resistant patient at relapse and in a novel RA-resistant cell line, NB4-MRA1. These cause altered binding to ligand and transcriptional coregulators, leading to a dominant-negative block of transcription of a retinoid-responsive element. The mutations we describe are in regions of the LBD that appear to be mutational "hot spots" occurring repeatedly in RA-resistant APL patient cells. We evaluated whether the histone deacetylase (HDAC) inhibition could overcome the effects of these mutations on RA-induced gene expression. Co-treatment with RA and TSA restored RARß gene expression in NB4-MRA1 cells, whose PML/RAR mutation is in helix 12 of the LBD, but not in an APL cell line harboring the patient-derived PML/RAR mutation, which was between helix 5 and 6. Furthermore, RA combined with TSA increases histone 4 acetylation on the RARß promoter only in NB4-MRA1 cells. Consistent with these results, the combined treatment induces differentiation of NB4-MRA1 only. Thus, the ability of an HDAC inhibitor to restore RA sensitivity in resistant cells may depend on their specific molecular defects. The variety of PML/RAR mutations arising in RA-resistant patients begins to explain how relapsed APL patients may differ in response to "transcription therapy" with HDAC inhibitors.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
M. Bots and R. W. Johnstone
Rational Combinations Using HDAC Inhibitors
Clin. Cancer Res.,
June 15, 2009;
15(12):
3970 - 3977.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. H. Dashwood
Xenobiotic Metabolism Relevance to Cancer
J. Nutr.,
October 1, 2006;
136(10):
2681S - 2682S.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. H. Dashwood, M. C. Myzak, and E. Ho
Dietary HDAC inhibitors: time to rethink weak ligands in cancer chemoprevention?
Carcinogenesis,
February 1, 2006;
27(2):
344 - 349.
[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]
|
|
|
|
|
|
|
M. Witcher, H. Y. Shiu, Q. Guo, and W. H. Miller Jr
Combination of retinoic acid and tumor necrosis factor overcomes the maturation block in a variety of retinoic acid-resistant acute promyelocytic leukemia cells
Blood,
November 15, 2004;
104(10):
3335 - 3342.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Parrella, M. Gianni', V. Cecconi, E. Nigro, M. M. Barzago, A. Rambaldi, C. Rochette-Egly, M. Terao, and E. Garattini
Phosphodiesterase IV Inhibition by Piclamilast Potentiates the Cytodifferentiating Action of Retinoids in Myeloid Leukemia Cells: CROSS-TALK BETWEEN THE cAMP AND THE RETINOIC ACID SIGNALING PATHWAYS
J. Biol. Chem.,
October 1, 2004;
279(40):
42026 - 42040.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. K. Mann, A. Rephaeli, A. L. Colosimo, Z. Diaz, A. Nudelman, I. Levovich, Y. Jing, S. Waxman, and W. H. Miller Jr.
A Retinoid/Butyric Acid Prodrug Overcomes Retinoic Acid Resistance in Leukemias by Induction of Apoptosis
Mol. Cancer Res.,
October 1, 2003;
1(12):
903 - 912.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Farboud, H. Hauksdottir, Y. Wu, and M. L. Privalsky
Isotype-Restricted Corepressor Recruitment: a Constitutively Closed Helix 12 Conformation in Retinoic Acid Receptors {beta} and {gamma} Interferes with Corepressor Recruitment and Prevents Transcriptional Repression
Mol. Cell. Biol.,
April 15, 2003;
23(8):
2844 - 2858.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
