Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia.
Acute promyelocytic leukemia (APL) is associated with the t(15;17) translocation, which generates a PML/RAR alpha fusion protein between PML, a growth suppressor localized on nuclear matrix-associated bodies, and RAR alpha, a nuclear receptor for retinoic acid (RA). PML/RAR alpha was proposed to block myeloid differentiation through inhibition of nuclear receptor response, as does a dominant negative RAR alpha mutant. In addition, in APL cells, PML/RAR alpha displaces PML and other nuclear body (NB) antigens onto nuclear microspeckles, likely resulting in the loss of PML and/or NB functions. RA leads to clinical remissions through induction of terminal differentiation, for which the respective contributions of RAR alpha (or PML/RAR alpha) activation, PML/RAR alpha degradation, and restoration of NB antigens localization are poorly determined. Arsenic trioxide also leads to remissions in APL patients, presumably through induction of apoptosis. We demonstrate that in non-APL cells, arsenic recruits the nucleoplasmic form of several NB antigens onto NB, but induces the degradation of PML only, identifying a powerful tool to approach NB function. In APL cells, arsenic targets PML and PML/RAR alpha onto NB and induces their degradation. Thus, RA and arsenic target RAR alpha and PML, respectively, but both induce the degradation of the PML/RAR alpha fusion protein, which should contribute to their therapeutic effects. The difference in the cellular events triggered by these two agents likely stems from RA-induced transcriptional activation and arsenic effects on NB proteins.
Zhu
J
J
Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, China.
Koken
M H
MH
Quignon
F
F
Chelbi-Alix
M K
MK
Degos
L
L
Wang
Z Y
ZY
Chen
Z
Z
de Thé
H
H
D017209:Apoptosis / Q000187:drug effects; D001151:Arsenic / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D009363:Neoplasm Proteins / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*
D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D001151:Arsenic