title: Calcium and calcineurin-NFAT signaling regulate granulocyte-monocyte progenitor cell cycle via Flt3-L.
abstract: Maintenance of myeloid progenitor cells is controlled by complex regulatory mechanisms and is orchestrated by multiple different transcription factors. Here, we report that the activation of the transcription factor nuclear factor of activated T cells (NFAT) by calcium-sensing protein calcineurin inhibits the proliferation of myeloid granulocyte-monocyte progenitors (GMPs). Myeloid progenitor subtypes exhibit variable sensitivity to induced Ca(2+) entry and consequently display differential engagement of the calcineurin-NFAT pathway. This study shows that inhibition of the calcineurin-NFAT pathway enhances the proliferation of GMPs both in vitro and in vivo and demonstrates that calcineurin-NFAT signaling in GMPs is initiated by Flt3-L. Inhibition of the calcineurin-NFAT pathway modified expression of the cell cycle regulation genes Cdk4, Cdk6, and Cdkn1a (p21), thus enabling rapid cell cycle progression specifically in GMPs. NFAT inhibitor drugs are extensively used in the clinic to restrict the pathological activation of lymphoid cells, and our data reveal for the first time that these therapies also exert potent effects on maintenance of the myeloid cell compartment through specific regulation of GMP proliferation.
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Jan
authors.initials: J
authors.lastname: Fric
authors.forename: Clarice X F
authors.initials: CX
authors.lastname: Lim
authors.forename: Alexandra
authors.initials: A
authors.lastname: Mertes
authors.forename: Bernett T K
authors.initials: BT
authors.lastname: Lee
authors.forename: Elena
authors.initials: E
authors.lastname: Viganò
authors.forename: Jinmiao
authors.initials: J
authors.lastname: Chen
authors.forename: Francesca
authors.initials: F
authors.lastname: Zolezzi
authors.forename: Michael
authors.initials: M
authors.lastname: Poidinger
authors.forename: Anis
authors.initials: A
authors.lastname: Larbi
authors.forename: Herbert
authors.initials: H
authors.lastname: Strobl
authors.forename: Teresa
authors.initials: T
authors.lastname: Zelante
authors.forename: Paola
authors.initials: P
authors.lastname: Ricciardi-Castagnoli
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D006098:Granulocytes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism*; D022423:Myeloid Cells / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D050778:NFATC Transcription Factors; C084881:flt3 ligand protein; D019703:Calcineurin; D002118:Calcium
keywords: Cyclosporine A; Flt3 signaling; Hematopoiesis; Myeloid differentiation; Tacrolimus
references.citation: Cell. 1991 Jun 28;65(7):1143-52
references.pmid: 1648448
references.citation: Blood. 2007 Feb 1;109(3):971-9
references.pmid: 17018855
references.citation: Leukemia. 1998 Sep;12(9):1333-7
references.pmid: 9737679
references.citation: Nature. 2013 Jul 11;499(7457):238-42
references.pmid: 23792561
references.citation: Blood. 2002 Sep 1;100(5):1532-42
references.pmid: 12176867
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7034-9
references.pmid: 19351896
references.citation: Biochem Biophys Res Commun. 2003 Nov 28;311(4):1117-32
references.pmid: 14623298
references.citation: Am J Transplant. 2010 Dec;10(12):2604-14
references.pmid: 21114641
references.citation: Genes Dev. 2003 Sep 15;17(18):2205-32
references.pmid: 12975316
references.citation: Blood. 1995 May 15;85(10):2747-55
references.pmid: 7537980
references.citation: Exp Hematol. 2007 May;35(5):757-70
references.pmid: 17577925
references.citation: Nature. 1997 Apr 24;386(6627):855-8
references.pmid: 9126747
references.citation: EMBO Rep. 2008 Nov;9(11):1141-8
references.pmid: 18818667
references.citation: Blood. 1997 Aug 15;90(4):1425-34
references.pmid: 9269760
references.citation: Int J Hematol. 2005 Aug;82(2):93-9
references.pmid: 16146838
references.citation: Blood. 2013 Apr 18;121(16):3205-15
references.pmid: 23446734
references.citation: J Leukoc Biol. 2004 Nov;76(5):1057-65
references.pmid: 15292278
references.citation: Immunity. 2001 Oct;15(4):659-69
references.pmid: 11672547
references.citation: Cell. 2005 Apr 22;121(2):295-306
references.pmid: 15851035
references.citation: Cell Death Dis. 2011 Jun 02;2:e165
references.pmid: 21633388
references.citation: J Biol Chem. 2010 Jan 29;285(5):3510-23
references.pmid: 19933579
references.citation: Nature. 1998 Mar 12;392(6672):182-6
references.pmid: 9515963
references.citation: Exp Hematol. 2007 Mar;35(3):394-406
references.pmid: 17309820
references.citation: Nat Rev Genet. 2008 Feb;9(2):115-28
references.pmid: 18202695
references.citation: Cell. 2001 Jun 29;105(7):863-75
references.pmid: 11439183
references.citation: Blood. 2000 Jun 1;95(11):3489-97
references.pmid: 10828034
references.citation: J Cell Physiol. 1998 Jul;176(1):57-66
references.pmid: 9618145
references.citation: Cell Stem Cell. 2011 Sep 2;9(3):262-71
references.pmid: 21885021
references.citation: Cell. 2001 Nov 30;107(5):617-29
references.pmid: 11733061
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9575-80
references.pmid: 11493684
references.citation: J Biol Chem. 2012 Oct 19;287(43):36291-304
references.pmid: 22893700
references.citation: J Cell Biochem. 2014 Jan;115(1):42-51
references.pmid: 24038146
references.citation: J Exp Med. 2003 Jul 21;198(2):293-303
references.pmid: 12874262
references.citation: Mol Cell. 1998 Apr;1(5):627-37
references.pmid: 9660947
references.citation: Front Immunol. 2012 Jun 18;3:161
references.pmid: 22719740
references.citation: J Exp Med. 2003 Jul 21;198(2):305-13
references.pmid: 12874263
references.citation: Blood. 2009 Sep 3;114(10):2172-80
references.pmid: 19587381
references.citation: Blood. 1993 Mar 1;81(5):1179-83
references.pmid: 7680241
references.citation: Trends Biochem Sci. 2005 Dec;30(12):688-97
references.pmid: 16260143
references.citation: EMBO Mol Med. 2012 Apr;4(4):269-82
references.pmid: 22311511
references.citation: Nature. 2007 Nov 29;450(7170):731-5
references.pmid: 18046413
references.citation: Blood. 2010 Jun 17;115(24):5061-8
references.pmid: 20393130
references.citation: Nat Rev Immunol. 2007 Sep;7(9):690-702
references.pmid: 17703229
references.citation: Immunol Rev. 2009 Sep;231(1):241-56
references.pmid: 19754901
references.citation: Cell Stem Cell. 2011 Jan 7;8(1):46-58
references.pmid: 21211781
references.citation: Blood. 2012 Aug 16;120(7):1380-9
references.pmid: 22611159
references.citation: Curr Opin Genet Dev. 2006 Oct;16(5):496-501
references.pmid: 16919448
references.citation: Science. 1995 Sep 8;269(5229):1427-9
references.pmid: 7660125
references.citation: Mol Cell. 2002 Nov;10(5):1071-81
references.pmid: 12453415
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14541-6
references.pmid: 11724967
references.citation: Haematologica. 2011 Nov;96(11):1580-8
references.pmid: 21750088
references.citation: J Exp Med. 2012 Feb 13;209(2):379-93
references.pmid: 22312110
references.citation: Cell Stem Cell. 2012 Sep 7;11(3):346-58
references.pmid: 22958930
references.citation: Immunol Rev. 2010 Mar;234(1):45-54
references.pmid: 20193011
references.citation: J Exp Med. 2005 Dec 5;202(11):1599-611
references.pmid: 16330818
references.citation: J Exp Med. 2010 May 10;207(5):923-31
references.pmid: 20421389
references.citation: Int Immunol. 2008 Sep;20(9):1211-8
references.pmid: 18644831
references.citation: Cell. 1999 Mar 5;96(5):611-4
references.pmid: 10089876
references.citation: Immunity. 1995 Jul;3(1):147-61
references.pmid: 7621074
references.citation: Trends Immunol. 2011 Feb;32(2):57-65
references.pmid: 21233016
references.citation: Cancer Cell. 2007 Oct;12(4):367-80
references.pmid: 17936561
references.citation: Cell. 2008 Jan 25;132(2):299-310
references.pmid: 18243104
references.citation: Cell Stem Cell. 2011 Jul 8;9(1):64-73
references.pmid: 21726834
references.citation: Cell Cycle. 2007 Jul 15;6(14):1789-95
references.pmid: 17637565
references.citation: J Cell Physiol. 2011 Jul;226(7):1780-92
references.pmid: 21506110
references.citation: Immunol Rev. 2013 Mar;252(1):12-23
references.pmid: 23405892
references.citation: Nature. 2009 Jul 9;460(7252):264-8
references.pmid: 19525933
references.citation: Blood. 2008 Apr 1;111(7):3849-58
references.pmid: 18245664
references.citation: Blood. 2002 Jan 1;99(1):310-8
references.pmid: 11756186
references.citation: J Exp Med. 2006 Jan 23;203(1):227-38
references.pmid: 16418395
references.citation: J Exp Med. 2013 Nov 18;210(12):2597-610
references.pmid: 24190429
references.citation: J Biol Chem. 2008 Nov 14;283(46):31909-19
references.pmid: 18775989
references.citation: Nat Immunol. 2008 Jun;9(6):676-83
references.pmid: 18469816
references.citation: Nat Med. 2013 Jun;19(6):730-8
references.pmid: 23685841
references.citation: FASEB J. 2002 Dec;16(14):1940-2
references.pmid: 12368232
references.citation: Nat Rev Immunol. 2005 Jun;5(6):472-84
references.pmid: 15928679