Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells

被引：99

作者：

El Hajj, Hiba ^{[1
,2
]}

Dassouki, Zeina ^{[1
,3
]}

Berthier, Caroline ^{[4
,5
]}

Raffoux, Emmanuel ^{[6
]}

Ades, Lionel ^{[7
,8
]}

Legrand, Olivier ^{[9
,10
,11
]}

Hleihel, Rita ^{[1
,3
]}

Sahin, Umut ^{[4
,5
]}

Tawil, Nadim ^{[1
,2
]}

Salameh, Ala ^{[1
,2
]}

Zibara, Kazem ^{[12
]}

Darwiche, Nadine ^{[13
]}

Mohty, Mohamad ^{[9
,10
,11
]}

Dombret, Herve ^{[6
]}

Fenaux, Pierre ^{[7
,8
]}

de The, Hugues ^{[4
,5
]}

Bazarbachi, Ali ^{[1
,3
]}

机构：

[1] Amer Univ Beirut, Dept Internal Med, Beirut, Lebanon

[2] Amer Univ Beirut, Dept Expt Pathol Microbiol & Immunol, Beirut, Lebanon

[3] Amer Univ Beirut, Dept Cell Biol Anat & Physiol Sci, Beirut, Lebanon

[4] Univ Paris Diderot, Coll France, Unites Mixtes Rech 944 7212, INSERM,Ctr Natl Rech Sci, Paris, France

[5] Equipe Labellisee Ligue Canc, Paris, France

[6] Hop St Louis, Serv Hematol Clin, F-75475 Paris 10, France

[7] Hop St Louis, Serv Hematol Senior, F-75475 Paris 10, France

[8] Hop Avicenne, Serv Hematol Clin, F-93009 Bobigny, France

[9] Hop St Antoine, INSERM, U938, F-75571 Paris, France

[10] Hop St Antoine, Serv Hematol, F-75571 Paris, France

[11] Univ Paris 06, Paris, France

[12] Lebanese Univ, Fac Sci, Lab Stem Cells, ER045,Dept Biol, Beirut, Lebanon

[13] Amer Univ Beirut, Dept Biochem & Mol Genet, Beirut, Lebanon

来源：

BLOOD | 2015年 / 125卷 / 22期

基金：

欧洲研究理事会;

关键词：

ACUTE MYELOID-LEUKEMIA; MUTANT NUCLEOPHOSMIN; MUTATIONS; PML; CHEMOTHERAPY; SUMOYLATION; COMBINATION; ACTIVATION; SYNERGY; TRIAL;

D O I：

10.1182/blood-2014-11-612416

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Nucleophosmin-1 (NPM1) is the most frequently mutated gene in acute myeloid leukemia (AML). Addition of retinoic acid (RA) to chemotherapy was proposed to improve survival of some of these patients. Here, we found that RA or arsenic trioxide synergistically induce proteasomal degradation of mutant NPM1 in AML cell lines or primary samples, leading to differentiation and apoptosis. NPM1 mutation not only delocalizes NPM1 from the nucleolus, but it also disorganizes promyelocytic leukemia (PML) nuclear bodies. Combined RA/arsenic treatment significantly reduced bone marrow blasts in 3 patients and restored the subnuclear localization of both NPM1 and PML. These findings could explain the proposed benefit of adding RA to chemotherapy in NPM1 mutant AMLs, and warrant a broader clinical evaluation of regimen comprising a RA/arsenic combination.

引用

页码：3447 / 3454

页数：8

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