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-trans retinoic acid and histone deacetylase inhibitors in vitro and in vivo Journal Article
| Authors: | Zhou, D.; Kim, S. H.; Ding, W.; Schultz, C.; Warrell, R. P. Jr; Gallagher, R. E. |
| Article Title: | 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-trans retinoic acid and histone deacetylase inhibitors in vitro and in vivo |
| Abstract: | 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 (Arg272GIn; 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. © 2002 by The American Society of Hematology. |
| Keywords: | clinical article; controlled study; treatment outcome; unclassified drug; gene mutation; missense mutation; mutation, missense; histone deacetylase inhibitor; cancer recurrence; protein domain; enzyme inhibition; antineoplastic combined chemotherapy protocols; neoplasm proteins; protein binding; recurrence; gene function; cell differentiation; mutational analysis; monoclonal antibody; arsenic trioxide; leukemia, promyelocytic, acute; cancer regression; correlation analysis; enzyme inhibitors; gene identification; drug response; promyelocytic leukemia; oncogene proteins, fusion; ligand; cell isolation; hydroxamic acids; gene control; binding sites; dna mutational analysis; codon; histone deacetylases; retinoic acid; ligand binding; arylbutyric acid derivative; butyric acid; trichostatin a; enhancer region; retinoic acid receptor alpha; tretinoin; hum 195; trans-activation (genetics); phenylbutyrates; butyrates; monoclonal antibody cd33; humans; prognosis; human; priority journal; article |
| Journal Title: | Blood |
| Volume: | 99 |
| Issue: | 4 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2002-02-15 |
| Start Page: | 1356 |
| End Page: | 1363 |
| Language: | English |
| DOI: | 10.1182/blood.V99.4.1356 |
| PUBMED: | 11830487 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 14 November 2014 -- Source: Scopus |
