Abstract:
:The induction of the granulocytic differentiation of leukemic cells by all-trans retinoic acid (RA) has been a major breakthrough in terms of survival for acute promyelocytic leukemia (APL) patients. Here we highlight the synergism and the underlying novel mechanism between RA and the granulocyte colony-stimulating factor (G-CSF) to restore differentiation of RA-refractory APL blasts. First, we show that in RA-refractory APL cells (UF-1 cell line), PML-RA receptor alpha (RARα) is not released from target promoters in response to RA, resulting in the maintenance of chromatin repression. Consequently, RARα cannot be recruited, and the RA target genes are not activated. We then deciphered how the combination of G-CSF and RA successfully restored the activation of RA target genes to levels achieved in RA-sensitive APL cells. We demonstrate that G-CSF restores RARα recruitment to target gene promoters through the activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and the subsequent derepression of chromatin. Thus, combinatorial activation of cytokines and RARs potentiates transcriptional activity through epigenetic modifications induced by specific signaling pathways.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Cassinat B,Zassadowski F,Ferry C,Llopis L,Bruck N,Lainey E,Duong V,Cras A,Despouy G,Chourbagi O,Beinse G,Fenaux P,Rochette Egly C,Chomienne Cdoi
10.1128/MCB.00756-10subject
Has Abstractpub_date
2011-04-01 00:00:00pages
1409-18issue
7eissn
0270-7306issn
1098-5549pii
MCB.00756-10journal_volume
31pub_type
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