DOI: 10.1182/blood.v99.4.1356. 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

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

10.1182/blood.v99.4.1356

Crossref journal-article

American Society of Hematology

Blood (234)

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 (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.

Bibliography

Zhou, D.-C., Kim, S. H., Ding, W., Schultz, C., Warrell, R. P., & Gallagher, R. E. (2002). Frequent mutations in the ligand-binding domain of PML-RARÎ± 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, 99(4), 1356â1363.

Authors 6

Da-Cheng Zhou (first)
Soon H. Kim (additional)
Wei Ding (additional)
Cynthia Schultz (additional)
Raymond P. Warrell (additional)
Robert E. Gallagher (additional)

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Dates

Type	When
Created	23 years, 1 month ago (July 27, 2002, 4:46 a.m.)
Deposited	5 years, 6 months ago (Feb. 12, 2020, 4:21 p.m.)
Indexed	2 months, 3 weeks ago (June 6, 2025, 5:08 a.m.)
Issued	23 years, 6 months ago (Feb. 15, 2002)
Published	23 years, 6 months ago (Feb. 15, 2002)
Published Print	23 years, 6 months ago (Feb. 15, 2002)

Funders 0

None

BibTeX

@article{Zhou_2002, 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-transretinoic acid and histone deacetylase inhibitors in vitro and in vivo}, volume={99}, ISSN={0006-4971}, url={http://dx.doi.org/10.1182/blood.v99.4.1356}, DOI={10.1182/blood.v99.4.1356}, number={4}, journal={Blood}, publisher={American Society of Hematology}, author={Zhou, Da-Cheng and Kim, Soon H. and Ding, Wei and Schultz, Cynthia and Warrell, Raymond P. and Gallagher, Robert E.}, year={2002}, month=feb, pages={1356–1363} }

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