New role for granulocyte colony-stimulating factor-induced extracellular signal-regulated kinase 1/2 in histone modification and retinoic acid receptor α recruitment to gene promoters: relevance to acute promyelocytic leukemia cell differentiation.
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.
INSERM UMR-S-940, Université Paris Diderot, Hopital Saint-Louis, 75010 Paris, France. bruno.cassinat@sls.aphp.fr
B
B
Cassinat
F
F
Zassadowski
C
C
Ferry
L
L
Llopis
N
N
Bruck
E
E
Lainey
V
V
Duong
A
A
Cras
G
G
Despouy
O
O
Chourbagi
G
G
Beinse
P
P
Fenaux
C
C
Rochette Egly
C
C
Chomienne
D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis; D048053:Mitogen-Activated Protein Kinase 6 / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology
D006657:Histones; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D016179:Granulocyte Colony-Stimulating Factor; D014212:Tretinoin; D048049:Extracellular Signal-Regulated MAP Kinases; D048052:Mitogen-Activated Protein Kinase 3; D048053:Mitogen-Activated Protein Kinase 6
EMBO J. 2009 Jan 7;28(1):34-47
19078967
J Immunol. 1998 May 15;160(10):4979-87
9590246
Oncogene. 2007 Jun 7;26(27):4018-24
17213810
Blood. 1999 Jul 1;94(1):39-45
10381496
Mol Biol Cell. 2006 Feb;17(2):566-75
16280361
Blood. 2002 Oct 1;100(7):2586-96
12239173
Blood. 1996 Sep 1;88(5):1824-33
8781440
Exp Cell Res. 1992 Aug;201(2):335-46
1322315
Genes Dev. 2000 Jan 15;14(2):121-41
10652267
Mol Endocrinol. 2006 Sep;20(9):2109-21
16613989
Blood. 1996 Aug 1;88(3):761-77
8704229
Exp Hematol. 2001 Jul;29(7):864-72
11438209
Blood. 2000 Mar 1;95(5):1656-62
10688821
Blood. 1994 Apr 1;83(7):1909-21
7511442
Oncogene. 2001 Oct 29;20(49):7154-60
11704844
Nucleic Acids Res. 1992 Dec 11;20(23):6393-9
1335571
Blood. 2009 Jul 16;114(3):600-7
19458357
Biochim Biophys Acta. 2011 Aug;1812(8):818-23
20970499
J Biol Chem. 2005 Sep 23;280(38):32565-8
16076839
Nature. 1995 Dec 14;378(6558):681-9
7501014
Mol Cell Biol. 2008 Oct;28(19):5912-23
18644863
Nature. 2000 Mar 9;404(6774):193-7
10724173
Oncogene. 2007 Oct 15;26(47):6715-23
17934480
Nucl Recept Signal. 2009 Oct 02;7:e008
20087429
Blood. 2001 Nov 1;98(9):2862-4
11675363
Blood. 2005 Jan 1;105(1):341-9
15339853
Nucl Recept Signal. 2009 May 08;7:e005
19471584
Mol Cell Biol. 2004 Dec;24(24):10954-64
15572696
Nat Rev Immunol. 2007 Feb;7(2):105-17
17259967
Nat Rev Drug Discov. 2006 Jan;5(1):37-50
16485345
Oncogene. 2007 Oct 15;26(47):6816-28
17934488
Mol Cell. 2006 Nov 3;24(3):367-81
17081988
J Biol Chem. 2002 Jul 12;277(28):24859-62
12032135
Cancer Cell. 2010 Feb 17;17(2):173-85
20159609
Leukemia. 2010 Feb;24(2):473-6
19865110
Blood. 2002 Feb 15;99(4):1356-63
11830487
Blood. 1998 Jul 15;92(2):374-82
9657734
Blood. 1990 Nov 1;76(9):1704-9
2224119
Leuk Res. 2004 May;28(5):525-32
15068906
Blood. 2004 Nov 15;104(10):3335-42
15256426
Blood. 1998 Aug 15;92(4):1172-83
9694705
Oncogene. 1994 Feb;9(2):545-51
8290265
Science. 2006 Jul 28;313(5786):449-51
16873633
Cancer Res. 2006 Jul 1;66(13):6763-71
16818652