Leukemia-associated retinoic acid receptor alpha fusion partners, PML and PLZF, heterodimerize and colocalize to nuclear bodies.
In acute promyelocytic leukemia (APL), the typical t(15;17) and the rare t(11;17) translocations express, respectively, the PML/RARalpha and PLZF/RARalpha fusion proteins (where RARalpha is retinoic acid receptor alpha). Herein, we demonstrate that the PLZF and PML proteins interact with each other and colocalize onto nuclear bodies (NBs). Furthermore, induction of PML expression by interferons leads to a recruitment of PLZF onto NBs without increase in the levels of the PLZF protein. PML/RARalpha and PLZF/RARalpha localize to the same microspeckled nuclear domains that appear to be common targets for the two fusion proteins in APL. Although PLZF/RARalpha does not affect the localization of PML, PML/RARalpha delocalizes the endogenous PLZF protein in t(15;17)-positive NB4 cells, pointing to a hierarchy in the nuclear targeting of these proteins. Thus, our results unify the molecular pathogenesis of APL with at least two different RARalpha gene translocations and stress the importance of alterations of PLZF and RARalpha nuclear localizations in this disease.
Koken
M H
MH
Centre National de la Recherche Scientifique, Unité Propre de Recherche 9051, Laboratoire Associé au Comité de Paris de la Ligue Contre le Cancer, Institut d'Hématologie, Hôpital St. Louis, 75475 Paris Cedex 10, France.
Reid
A
A
Quignon
F
F
Chelbi-Alix
M K
MK
Davies
J M
JM
Kabarowski
J H
JH
Zhu
J
J
Dong
S
S
Chen
S
S
Chen
Z
Z
Tan
C C
CC
Licht
J
J
Waxman
S
S
de Thé
H
H
Zelent
A
A
D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism*; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins