PMID- 9486654
OWN - NLM
STAT- MEDLINE
DCOM- 19980309
LR  - 20220408
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 391
IP  - 6669
DP  - 1998 Feb 19
TI  - Role of the histone deacetylase complex in acute promyelocytic leukaemia.
PG  - 811-4
AB  - Non-liganded retinoic acid receptors (RARs) repress transcription of target genes 
      by recruiting the histone deacetylase complex through a class of silencing 
      mediators termed SMRT or N-CoR. Mutant forms of RARalpha, created by chromosomal 
      translocations with either the PML (for promyelocytic leukaemia) or the PLZF (for 
      promyelocytic leukaemia zinc finger) locus, are oncogenic and result in human 
      acute promyelocytic leukaemia (APL). PML-RARalpha APL patients achieve complete 
      remission following treatments with pharmacological doses of retinoic acids (RA); 
      in contrast, PLZF-RARalpha patients respond very poorly, if at all. Here we 
      report that the association of these two chimaeric receptors with the histone 
      deacetylase (HDAC) complex helps to determine both the development of APL and the 
      ability of patients to respond to retinoids. Consistent with these observations, 
      inhibitors of histone deacetylase dramatically potentiate retinoid-induced 
      differentiation of RA-sensitive, and restore retinoid responses of RA-resistant, 
      APL cell lines. Our findings suggest that oncogenic RARs mediate leukaemogenesis 
      through aberrant chromatin acetylation, and that pharmacological manipulation of 
      nuclear receptor co-factors may be a useful approach in the treatment of human 
      disease.
FAU - Lin, R J
AU  - Lin RJ
AD  - Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La 
      Jolla, California 92037, USA.
FAU - Nagy, L
AU  - Nagy L
FAU - Inoue, S
AU  - Inoue S
FAU - Shao, W
AU  - Shao W
FAU - Miller, W H Jr
AU  - Miller WH Jr
FAU - Evans, R M
AU  - Evans RM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Antineoplastic Agents)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Hydroxamic Acids)
RN  - 0 (NCOR2 protein, human)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Nuclear Receptor Co-Repressor 2)
RN  - 0 (Oncogene Proteins, Fusion)
RN  - 0 (RARA protein, human)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Repressor Proteins)
RN  - 0 (Retinoic Acid Receptor alpha)
RN  - 0 (SIN3 protein, S cerevisiae)
RN  - 0 (SIN3A transcription factor)
RN  - 0 (Saccharomyces cerevisiae Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 3X2S926L3Z (trichostatin A)
RN  - 5688UTC01R (Tretinoin)
RN  - EC 3.5.1.98 (Histone Deacetylases)
RN  - EC 3.5.1.98 (Sin3 Histone Deacetylase and Corepressor Complex)
SB  - IM
MH  - Antineoplastic Agents/metabolism/therapeutic use
MH  - Cell Line
MH  - Cloning, Molecular
MH  - DNA-Binding Proteins/genetics/metabolism
MH  - Drug Resistance, Neoplasm
MH  - Enzyme Inhibitors/pharmacology
MH  - Escherichia coli
MH  - Hematopoiesis
MH  - Histone Deacetylase Inhibitors
MH  - Histone Deacetylases/*metabolism
MH  - Hydroxamic Acids/pharmacology
MH  - Leukemia, Promyelocytic, Acute/drug therapy/*enzymology
MH  - Neoplasm Proteins/genetics/metabolism
MH  - *Nuclear Proteins
MH  - Nuclear Receptor Co-Repressor 2
MH  - Oncogene Proteins, Fusion/genetics/metabolism
MH  - Receptors, Retinoic Acid/genetics/metabolism
MH  - Repressor Proteins/metabolism
MH  - Retinoic Acid Receptor alpha
MH  - Saccharomyces cerevisiae/genetics
MH  - *Saccharomyces cerevisiae Proteins
MH  - Sin3 Histone Deacetylase and Corepressor Complex
MH  - Transcription Factors/genetics/metabolism
MH  - Tretinoin/metabolism/therapeutic use
MH  - Tumor Suppressor Proteins
EDAT- 1998/03/05 03:03
MHDA- 2001/03/23 10:01
CRDT- 1998/03/05 03:03
PHST- 1998/03/05 03:03 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1998/03/05 03:03 [entrez]
AID - 10.1038/35895 [doi]
PST - ppublish
SO  - Nature. 1998 Feb 19;391(6669):811-4. doi: 10.1038/35895.