The PRC1 Polycomb group complex interacts with PLZF/RARA to mediate leukemic transformation.
Ectopic repression of retinoic acid (RA) receptor target genes by PML/RARA and PLZF/RARA fusion proteins through aberrant recruitment of nuclear corepressor complexes drives cellular transformation and acute promyelocytic leukemia (APL) development. In the case of PML/RARA, this repression can be reversed through treatment with all-trans RA (ATRA), leading to leukemic remission. However, PLZF/RARA ectopic repression is insensitive to ATRA, resulting in persistence of the leukemic diseased state after treatment, a phenomenon that is still poorly understood. Here we show that, like PML/RARA, PLZF/RARA expression leads to recruitment of the Polycomb-repressive complex 2 (PRC2) Polycomb group (PcG) complex to RA response elements. However, unlike PML/RARA, PLZF/RARA directly interacts with the PcG protein Bmi-1 and forms a stable component of the PRC1 PcG complex, resulting in PLZF/RARA-dependent ectopic recruitment of PRC1 to RA response elements. Upon treatment with ATRA, ectopic recruitment of PRC2 by either PML/RARA or PLZF/RARA is lost, whereas PRC1 recruited by PLZF/RARA remains, resulting in persistent RA-insensitive gene repression. We further show that Bmi-1 is essential for the PLZF/RARA cellular transformation property and implicates a central role for PRC1 in PLZF/RARA-mediated myeloid leukemic development.
Boukarabila
Hanane
H
Centre d'Immunologie de Marseille-Luminy (CIML), Université de la Méditerranée, Campus de Luminy, 13288 Marseille Cedex 09, France.
Saurin
Andrew J
AJ
Batsché
Eric
E
Mossadegh
Noushine
N
van Lohuizen
Maarten
M
Otte
Arie P
AP
Pradel
Jacques
J
Muchardt
Christian
C
Sieweke
Michael
M
Duprez
Estelle
E
D000970:Antineoplastic Agents / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic; D002843:Chromatin / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology; D020298:U937 Cells
D000970:Antineoplastic Agents; C069077:BMI1 protein, human; D002843:Chromatin; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C118318:PLZF-RARalpha fusion protein, human; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D014212:Tretinoin; D063150:Polycomb Repressive Complex 1