Altered ligand binding and transcriptional regulation by mutations in the PML/RARα ligand-binding domain arising in retinoic acid-resistant patients with acute promyelocytic leukemia

被引:59
作者
Côté, S
Zhou, DC
Bianchini, A
Nervi, C
Gallagher, RE
Miller, WH
机构
[1] Sir Mortimer B Davis Jewish Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada
[2] McGill Univ, Dept Oncol & Med, Montreal, PQ, Canada
[3] Montefiore Med Ctr, Bronx, NY 10467 USA
[4] Albert Einstein Canc Ctr, Bronx, NY USA
[5] Univ Roma La Sapienza, Dipartimento Istol & Embriol Med, Rome, Italy
关键词
D O I
10.1182/blood.V96.9.3200.h8003200_3200_3208
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 alpha, 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 alpha 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 alpha 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 alpha 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. (C) 2000 by The American Society of Hematology.
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页码:3200 / 3208
页数:9
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