Repression of Hepatocyte Nuclear Factor 4  by Tumor Suppressor p53: Involvement of the Ligand-Binding Domain and Histone Deacetylase Activity

2002 ◽  
Vol 16 (2) ◽  
pp. 402-410 ◽  
Author(s):  
Y. Maeda
Keyword(s):  
Tumor Suppressor ◽  
Ligand Binding ◽  
Histone Deacetylase ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Tumor Suppressor P53 ◽  
Hepatocyte Nuclear Factor 4

Frequent mutations in the ligand-binding domain of PML-RARα after multiple relapses of acute promyelocytic leukemia: analysis for functional relationship to response to all-transretinoic acid and histone deacetylase inhibitors in vitro and in vivo

Blood ◽  
2002 ◽  
Vol 99 (4) ◽  
pp. 1356-1363 ◽  
Author(s):  
Da-Cheng Zhou ◽  
Soon H. Kim ◽  
Wei Ding ◽  
Cynthia Schultz ◽  
Raymond P. Warrell ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Histone Deacetylase ◽  
Acute Promyelocytic Leukemia ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Promyelocytic Leukemia ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Missense Mutations

This study identified missense mutations in the ligand binding domain of the oncoprotein PML-RARα in 5 of 8 patients with acute promyelocytic leukemia (APL) with 2 or more relapses and 2 or more previous courses of all-trans retinoic acid (RA)–containing therapy. Four mutations were novel (Lys207Asn, Gly289Arg, Arg294Trp, and Pro407Ser), whereas one had been previously identified (Arg272Gln; normal RARα1 codon assignment). Five patients were treated with repeat RA plus phenylbutyrate (PB), a histone deacetylase inhibitor, and one patient experienced a prolonged clinical remission. Of the 5 RA + PB-treated patients, 4 had PML-RARα mutations. The Gly289Arg mutation in the clinical responder produced the most defective PML-RARα function in the presence of RA with or without sodium butyrate (NaB) or trichostatin A. Relapse APL cells from this patient failed to differentiate in response to RA but partially differentiated in response to NaB alone, which was augmented by RA. In contrast, NaB alone had no differentiation effect on APL cells from another mutant case (Pro407Ser) but enhanced differentiation induced by RA. These results indicate that PML-RARα mutations occurred with high frequency after multiple RA treatment relapses, indicate that the functional potential of PML-RARα was not correlated with clinical response to RA + PB treatment, and suggest that the response to RA + PB therapy in one patient was related to the ability of PB to circumvent the blocked RA-regulated gene response pathway.

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