Identification of the novel deletion-type PML-RARA mutation associated with the retinoic acid resistance in acute promyelocytic leukemia.
Hikaru HattoriYuichi IshikawaNaomi KawashimaAkimi AkashiYohei YamaguchiYasuhiko HaradaDaiki HiranoYoshiya AdachiKotaro MiyaoYoko UshijimaSeitaro TerakuraTetsuya NishidaTadashi MatsushitaHitoshi KiyoiPublished in: PloS one (2018)
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.
Keyphrases
- poor prognosis
- induced apoptosis
- rheumatoid arthritis
- cell cycle arrest
- case report
- bone marrow
- amino acid
- oxidative stress
- stem cells
- cell death
- endoplasmic reticulum stress
- heavy metals
- single cell
- intensive care unit
- ankylosing spondylitis
- respiratory failure
- risk assessment
- binding protein
- cancer therapy
- hepatitis b virus
- wild type
- cell therapy
- replacement therapy
- diabetic rats