Identification of the novel deletion-type PML-RARA mutation associated with the retinoic acid resistance in acute promyelocytic leukemia
All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are essential for acute promyelocytic leukemia (APL) treatment. It has been reported that mutations in PML-RARA confer resistance to ATRA and ATO, and are associated with poor prognosis. Although most PML-RARA mutations were point mutations,...
Saved in:
Published in | PloS one Vol. 13; no. 10; p. e0204850 |
---|---|
Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Public Library of Science
05.10.2018
Public Library of Science (PLoS) |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are essential for acute promyelocytic leukemia (APL) treatment. It has been reported that mutations in PML-RARA confer resistance to ATRA and ATO, and are associated with poor prognosis. Although most PML-RARA mutations were point mutations, we identified a novel seven amino acid deletion mutation (p.K227_T233del) in the RARA region of PML-RARA in a refractory APL patient. Here, we analyzed the evolution of the mutated clone and demonstrated the resistance of the mutated clone to retinoic acid (RA). Mutation analysis of PML-RARA was performed using samples from a chemotherapy- and ATRA-resistant APL patient, and the frequencies of mutated PML-RARA transcript were analyzed by targeted deep sequencing. To clarify the biological significance of the identified PML-RARA mutations, we analyzed the ATRA-induced differentiation and PML nuclear body formation in mutant PML-RARA-transduced HL-60 cells. At molecular relapse, the p.K227_T233del deletion and the p.R217S point-mutation in the RARA region of PML-RARA were identified, and their frequencies increased after re-induction therapy with another type of retinoiec acid (RA), tamibarotene. In deletion PML-RARA-transduced cells, the CD11b expression levels and NBT reducing ability were significantly decreased compared with control cells and the formation of PML nuclear bodies was rarely observed after RA treatment. These results indicate that this deletion mutation was closely associated with the disease progression during RA treatment. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing Interests: We have the following interests: Hitoshi Kiyoi received research funding, which is unrelated to this study, from Chugai Pharmaceutical Co. Ltd., Bristol-Myers Squibb, Kyowa Hakko Kirin Co. Ltd., Zenyaku Kogyo Co. Ltd., FUJIFILM Corporation, Nippon Boehringer Ingelheim Co. Ltd., Astellas Pharma Inc. and Celgene Corporation, consulting fees from Astellas Pharma Inc. and Daiichi Sankyo Co. Ltd., and honoraria from Bristol-Myers Squibb and Pfizer Japan Inc. The other authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials. |
ISSN: | 1932-6203 1932-6203 |
DOI: | 10.1371/journal.pone.0204850 |