Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia

Gallagher, Robert E.; Moser, Barry Kurt; Racevskis, Janis; Poiré, Xavier; Bloomfield, Clara D.; Carroll, Andrew J.; Ketterling, Rhett P.; Roulston, Diane; Schachter-Tokarz, Esther; Zhou, Da-Cheng; Chen, I-Ming L.; Harvey, Richard C.; Koval, Greg; Sher, Dorie; Feusner, James; Tallman, Martin S.; Larson, Richard A.; Powell, Bayard L.; Appelbaum, Frederick R.; Paietta, Elisabeth; Willman, Cheryl L.; Stock, Wendy

doi:10.1182/blood-2012-01-407601

Cited by 51 publications

(54 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additional genetic mutations in PML-RARa and another gene, such as FLT3-ITD or TP53 [66,85], may contribute to disease progression and drug resistance in APL. Detailed genomic analyses using clinical samples harvested repeatedly from patients may help for predicting prognosis, selecting effective targeting drugs, understanding molecular backgrounds, and designing sophisticated new therapeutic strategies.…”

Section: Resultsmentioning

confidence: 99%

“…These mutations accumulate in the three subregions (zones I, II, and III in Fig. 3) of the LBD domain [66]. Gallagher et al [66] reported that PML-RARa LBD mutation was confirmed 18 of 45 (40 %) relapse patients treated with ATRA/chemotherapy.…”

Section: Mechanisms Of Resistance To Atramentioning

confidence: 96%

“…3) of the LBD domain [66]. Gallagher et al [66] reported that PML-RARa LBD mutation was confirmed 18 of 45 (40 %) relapse patients treated with ATRA/chemotherapy. In vitro analyses using ATRA-resistant NB4 cells (NB4-R1, -R2 [67], -R4 [60], and -RA [61]) and mutated-PML-RARa expressing Cos-1 cells [65] indicated that ATRA binding affinity with mutated PML-RARa was generally lower than that with PML-RARa without mutations, due to conformational changes in LBD.…”

Section: Mechanisms Of Resistance To Atramentioning

confidence: 99%

“…Only genetic mutations on the RARa LBD domain in PML-RARa have been confirmed as an ATRAresistant mechanism, from both clinical observations and in vitro molecular analyses [59][60][61][62][63][64][65][66]. Genetic mutations (missense, nonsense, and deletions) on RARa LBD domain have been confirmed in ATRA-resistant patients and APL cell lines, which grow despite pharmacological concentrations of ATRA, as summarized in Fig.…”

Section: Mechanisms Of Resistance To Atramentioning

confidence: 99%

“…One patient with the M3 variant, expressing PML- [66]. Red letters indicate amino acids substituted in specific patients and/or cells.…”

Section: Molecular Mechanisms Of Resistance To As 2 Omentioning

confidence: 99%

See 4 more Smart Citations

Mechanisms of action and resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) in acute promyelocytic leukemia

2013

View full text Add to dashboard Cite

Since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (As 2 O 3 ) for the treatment of acute promyelocytic leukemia (APL), the overall survival rate has improved dramatically. However, relapse/refractory patients showing resistance to ATRA and/or As 2 O 3 are recognized as a clinically significant problem. Genetic mutations resulting in amino acid substitution in the retinoic acid receptor alpha (RARa) ligand binding domain (LBD) and the PML-B2 domain of PML-RARa, respectively, have been reported as molecular mechanisms underlying resistance to ATRA and As 2 O 3 . In the LBD mutation, ATRA binding with LBD is generally impaired, and ligand-dependent co-repressor dissociation and degradation of PML-RARa by the proteasome pathway, leading to cell differentiation, are inhibited. The PML-B2 mutation interferes with the direct binding of As 2 O 3 with PML-B2, and PML-RARa SUMOylation with As 2 O 3 followed by multimerization and degradation is impaired. To overcome ATRA resistance, utilization of As 2 O 3 provides a preferable outcome, and recently, a synthetic retinoid Am80, which has a higher binding affinity with PML-RARa than ATRA, has been tested in the clinical setting. However, no strategy attempted to date has been successful in overcoming As 2 O 3 resistance. Detailed genomic analyses using patient samples harvested repeatedly may help in predicting the prognosis, selecting the effective targeting drugs, and designing new sophisticated strategies for the treatment of APL.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Mechanisms Of Resistance To Atramentioning

confidence: 96%

Section: Mechanisms Of Resistance To Atramentioning

confidence: 99%

Section: Mechanisms Of Resistance To Atramentioning

confidence: 99%

“…One patient with the M3 variant, expressing PML- [66]. Red letters indicate amino acids substituted in specific patients and/or cells.…”

Section: Molecular Mechanisms Of Resistance To As 2 Omentioning

confidence: 99%

See 3 more Smart Citations

Mechanisms of action and resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) in acute promyelocytic leukemia

2013

View full text Add to dashboard Cite

show abstract

Retinoic Acid in Acute Myeloid Leukemias

Fenaux

2015

The Retinoids

View full text Add to dashboard Cite

Mutational landscape of patients with acute promyelocytic leukemia at diagnosis and relapse

et al. 2019

View full text Add to dashboard Cite

Despite the high probability of cure of patients with acute promyelocytic leukemia (APL), mechanisms of relapse are still largely unclear. Mutational profiling at diagnosis and/or relapse may help to identify APL patients needing frequent molecular monitoring and early treatment intervention. Using an NGS approach including a 31 myeloid gene-panel, we tested BM samples of 44 APLs at the time of diagnosis, and of 31 at relapse. Mutations in PML and RARA genes were studied using a customized-NGS-RNA panel. Patients relapsing after ATRA-chemotherapy rarely had additional mutations (P = .009). In patients relapsing after ATRA/ATO, the PML gene was a preferential mutation target. We then evaluated the predictive value of mutations at APL diagnosis. A median of two mutations was detectable in 9/11 patients who later relapsed, vs one mutation in 21/33 patients who remained in CCR (P = .0032). This corresponded to a significantly lower risk of relapse in patients with one or less mutations (HR 0.046; 95% CI 0.011-0.197; P < .0001). NGS-analysis at the time of APL diagnosis may inform treatment decisions, including alternative treatments for cases with an unfavorable mutation profile.

show abstract

Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia

Cited by 51 publications

References 41 publications

Mechanisms of action and resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) in acute promyelocytic leukemia

Mechanisms of action and resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) in acute promyelocytic leukemia

Retinoic Acid in Acute Myeloid Leukemias

Mutational landscape of patients with acute promyelocytic leukemia at diagnosis and relapse

Contact Info

Product

Resources

About