Varying responses of PML-RARA with different genetic mutations to arsenic trioxide.

Resistance to arsenic and/or all-trans retinoic acid (ATRA) is a challenging problem in the clinical management of acute promyelocytic leukemia (APL). Acquired genetic mutations in the PML moiety of the PML-RARA fusion gene are found in some patients with relapsed/refractory APL. Whether all of the identified point mutations play a role and have a similar function in the mechanisms of arsenic resistance remains unknown. Here we performed in vitro functional analyses and a retrospective analysis of APL patients to investigate the effect of PML-RARA mutations in mediating resistance to arsenic trioxide. Among the 5-point mutations in the PML part of PML-RARA identified in patients with relapsed APL, we found that A216V, S214L, and A216T mutations could attenuate the negative regulation of arsenic on PML-RARA, resulting in the retention of oncoproteins. In contrast, L217F and S220G mutations functioned weakly in this context. Furthermore, we demonstrated that either increasing the concentration of arsenic trioxide or combining it with ATRA could overcome the mutation-triggered arsenic resistance in vitro. In addition to presenting more evidence to reinforce the correlation of genetic mutations in PML-RARA with arsenic efficacy, we provide novel insight into the functional difference of acquired mutations of PML-RARA both in vitro and in the clinical setting. Our findings may help predict the prognosis and select more effective strategies during APL therapy.

Liu J ，Zhu HH ，Jiang H ，Jiang Q ，Huang XJ ... -  《-》

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

Lou Y ，Ma Y ，Sun J ，Ye X ，Pan H ，Wang Y ，Qian W ，Meng H ，Mai W ，He J ，Tong H ，Jin J ... -  《-》

Mutations at proximal cysteine residues in PML impair ATO binding by destabilizing the RBCC domain.

Dubey S ，Mishra N ，Shelke R ，Varma AK ... -  《-》

Missense mutations in PML-RARA are critical for the lack of responsiveness to arsenic trioxide treatment.

Goto E ，Tomita A ，Hayakawa F ，Atsumi A ，Kiyoi H ，Naoe T ... -  《-》

Missense mutations in the PML/RARalpha ligand binding domain in ATRA-resistant As(2)O(3) sensitive relapsed acute promyelocytic leukemia.

Marasca R ，Zucchini P ，Galimberti S ，Leonardi G ，Vaccari P ，Donelli A ，Luppi M ，Petrini M ，Torelli G ... -  《HAEMATOLOGICA》