PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3.

Abstract : As(2)O(3) cures acute promyelocytic leukemia (APL) by initiating PML/RARA oncoprotein degradation, through sumoylation of its PML moiety. However, how As(2)O(3) initiates PML sumoylation has remained largely unexplained. As(2)O(3) binds vicinal cysteines and increases reactive oxygen species (ROS) production. We demonstrate that upon As(2)O(3) exposure, PML undergoes ROS-initiated intermolecular disulfide formation and binds arsenic directly. Disulfide-linked PML or PML/RARA multimers form nuclear matrix-associated nuclear bodies (NBs), become sumoylated and are degraded. Hematopoietic progenitors transformed by an As(2)O(3)-binding PML/RARA mutant exhibit defective As(2)O(3) response. Conversely, nonarsenical oxidants elicit PML/RARA multimerization, NB-association, degradation, and leukemia response in vivo, but do not affect PLZF/RARA-driven APLs. Thus, PML oxidation regulates NB-biogenesis, while oxidation-enforced PML/RARA multimerization and direct arsenic-binding cooperate to enforce APL's exquisite As(2)O(3) sensitivity.
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Cancer Cell, Elsevier, 2010, 18 (1), pp.88-98. 〈10.1016/j.ccr.2010.06.003〉
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Contributeur : Catherine Bertignac <>
Soumis le : jeudi 15 décembre 2011 - 09:58:03
Dernière modification le : jeudi 11 janvier 2018 - 06:22:24

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Marion Jeanne, Valérie Lallemand-Breitenbach, Omar Ferhi, Marcel Koken, Morgane Le Bras, et al.. PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3.. Cancer Cell, Elsevier, 2010, 18 (1), pp.88-98. 〈10.1016/j.ccr.2010.06.003〉. 〈hal-00652202〉



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