Evaluating frequency of PML-RARA mutations and conferring resistance to arsenic trioxide-based therapy in relapsed acute promyelocytic leukemia patients

Lou, Yinjun; Ma, Yue; Sun, Jianai; Ye, Xiujin; Pan, Hanzhang; Wang, Yungui; Qian, W.; Meng, Haitao; Mai, Wenyuan; He, Jingsong; Tong, Hongyan; Jin, Jie

doi:10.1007/s00277-015-2477-x

Cited by 37 publications

(28 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A mutation in the same codon but with different amino acid substitution (A216V) has been recently reported in the unrearranged PML gene in a patient with ATO‐resistant APL (Lhemann‐Che et al , ). Several studies confirmed that mutations affecting the A216 amino acid residue of PML are frequent and may confer resistance to ATO (Lou et al , ). In keeping with this hypothesis, mutations of the PML‐B2 domain of PML/RARA have been shown to prevent ATO binding and inhibit degradation of the oncoprotein, thus hindering oligomerization into nuclear bodies (Goto et al , ).…”

Section: Resultsmentioning

confidence: 85%

Mutations affecting both the rearranged and the unrearranged PML alleles in refractory acute promyelocytic leukaemia

et al. 2016

View full text Add to dashboard Cite

Acute promyelocytic leukaemia (APL) is characterized by the PML/RARA fusion transcript. PML and RARA mutations have been shown to directly respond to arsenic trioxide (ATO) and all-trans retinoic (ATRA). We analysed the prevalence of PML mutations in 32 patients with de novo or therapy-related APL (t-APL; n = 5), treated with ATO. We identified one ATO-resistant t-APL patient, who presented a PML A216T mutation in both the rearranged and unrearranged PML alleles, and two mutations in the rearranged RARA gene. In this patient, subclones with different PML and RARA mutations acquired clonal dominance during the disease course, probably leading to treatment resistance.

show abstract

Section: Resultsmentioning

confidence: 85%

Mutations affecting both the rearranged and the unrearranged PML alleles in refractory acute promyelocytic leukaemia

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Our sensitive mutational analysis allowed the detection of a high prevalence of PML and RARA mutations in 27% of our patients, including 30 relapsed APLs. That is concordant with other studies, which described PML and RARA mutations in up to 47% of APL . All mutations described were localized in critical domains of PML and RARA , known to be associated to ATO and ATRA binding.…”

Section: Discussionmentioning

confidence: 56%

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

“…Although ATRA and arsenic have improved the overall survival rate of APL patients [35, 36], there exist major issues in the APL treatment such as ATRA and arsenic resistance as well as their off target side effects [18, 19, 37]. In our current study, we provided a potential drug lead that may overcome ATRA-resistance and ATRA-related side effects through its distinct acting mode.…”

Section: Discussionmentioning

confidence: 92%

“…Because arsenic targets to the PML moiety, it can overcome ATRA-resistance in some cases [13]. However, APL driven by the PLZF-RARα and PML-RARα with point mutations in the PML moiety such as A216V are resistant to arsenic [18, 19]. Thus, novel drugs with different therapeutic mechanisms are desperately needed to overcome the resistance and adverse effects of ATRA and/or arsenic.…”

Section: Introductionmentioning

confidence: 99%

RXRα ligand Z-10 induces PML-RARα cleavage and APL cell apoptosis through disrupting PML-RARα/RXRα complex in a cAMP-independent manner

Zeng

Zhang

et al. 2017

Oncotarget

View full text Add to dashboard Cite

The major oncogenic driver of acute promyelocytic leukemia (APL) is the fusion protein PML-RARα originated from the chromosomal translocation t(15;17). All-trans retinoic acid (ATRA) and arsenic trioxide cure most patients by directly targeting PML-RARα. However, major issues including the resistance of ATRA and arsenic therapy still remain in APL clinical management. Here we showed that compound Z-10, a nitro-ligand of retinoid X receptor α (RXRα), strongly promoted the cAMP-independent apoptosis of both ATRA- sensitive and resistant NB4 cells via the induction of caspase-mediated PML-RARα degradation. RXRα was vital for the stability of both PML-RARα and RARα likely through the interactions. The binding of Z-10 to RXRα dramatically inhibited the interaction of RXRα with PML-RARα but not with RARα, leading to Z-10's selective induction of PML-RARα but not RARα degradation. Z-36 and Z-38, two derivatives of Z-10, had improved potency of inducing PML-RARα reduction and NB4 cell apoptosis. Hence, RXRα ligand Z-10 and its derivatives could target both ATRA- sensitive and resistant APL cells through their distinct acting mechanism, and are potential drug leads for APL treatment.

show abstract

Evaluating frequency of PML-RARA mutations and conferring resistance to arsenic trioxide-based therapy in relapsed acute promyelocytic leukemia patients

Cited by 37 publications

References 29 publications

Mutations affecting both the rearranged and the unrearranged PML alleles in refractory acute promyelocytic leukaemia

Mutations affecting both the rearranged and the unrearranged PML alleles in refractory acute promyelocytic leukaemia

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

RXRα ligand Z-10 induces PML-RARα cleavage and APL cell apoptosis through disrupting PML-RARα/RXRα complex in a cAMP-independent manner

Contact Info

Product

Resources

About