title: Mesenchymal stem cells induce granulocytic differentiation of acute promyelocytic leukemic cells via IL-6 and MEK/ERK pathways.
abstract: All-trans retinoic acid (ATRA) induces clinical remission in most acute promyelocytic leukemia (APL) patients by inducing terminal differentiation of APL cells toward mature granulocytes. Here we report that human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are capable of inducing granulocytic differentiation of the APL-derived NB4 cell line as well as primary APL cells and also cooperate with ATRA in an additive manner. Transwell coculture experiments revealed that UC-MSCs' differentiation-inducing effect was mediated through some soluble factors. Differentiation attenuation by IL-6Ra neutralization and induction by addition of exogenous IL-6 confirmed that IL-6 secreted by UC-MSCs was at least partially responsible for this differentiation induction process. Moreover, we found that UC-MSCs activated the MEK/ERK signaling pathway in promyelocytic cells and pharmacological inhibition of the MEK/ERK pathway reversed UC-MSC-induced differentiation, indicating that UC-MSCs exerted effect through activation of the MEK/ERK signaling pathway. These results demonstrate for the first time a stimulatory effect of MSCs on the differentiation of APL cells and bring a new insight into the interaction between MSCs and leukemic cells. Our data suggest that UC-MSCs/ATRA combination could be used as a novel therapeutic strategy for APL patients.
authors: State Key Laboratory of Experimental Hematology, National Engineering Research Center of Stem Cells, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
authors: Fang
authors: F
authors: Chen
authors: Kang
authors: K
authors: Zhou
authors: Lei
authors: L
authors: Zhang
authors: Fengxia
authors: F
authors: Ma
authors: Dandan
authors: D
authors: Chen
authors: Junjie
authors: J
authors: Cui
authors: Xiaoming
authors: X
authors: Feng
authors: Shaoguang
authors: S
authors: Yang
authors: Ying
authors: Y
authors: Chi
authors: Zhibo
authors: Z
authors: Han
authors: Feng
authors: F
authors: Xue
authors: Lijuan
authors: L
authors: Rong
authors: Meili
authors: M
authors: Ge
authors: Li
authors: L
authors: Wan
authors: Shuxia
authors: S
authors: Xu
authors: Wenjing
authors: W
authors: Du
authors: Shihong
authors: S
authors: Lu
authors: Hongying
authors: H
authors: Ren
authors: Zhongchao
authors: Z
authors: Han
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D064987:Cell- and Tissue-Based Therapy; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology / Q000628:therapy*; D020935:MAP Kinase Signaling System / Q000235:genetics*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*; D014470:Umbilical Cord / Q000166:cytology / Q000187:drug effects
chemical_list: D015850:Interleukin-6; D014212:Tretinoin
references: Blood. 2002 Nov 15;100(10):3719-30
references: 12393712
references: Leukemia. 2007 Feb;21(2):304-10
references: 17170725
references: Leukemia. 2004 Aug;18(8):1373-9
references: 15190260
references: Blood. 2001 May 15;97(10):3234-43
references: 11342454
references: PLoS One. 2010 Jul 28;5(7):e11813
references: 20676365
references: Cell Physiol Biochem. 2010;26(6):799-808
references: 21220911
references: Biol Blood Marrow Transplant. 2007 Dec;13(12):1477-86
references: 18022578
references: J Cell Biochem. 2010 May;110(1):248-59
references: 20225236
references: J Cell Physiol. 2000 Jul;184(1):58-69
references: 10825234
references: Exp Hematol. 2006 Nov;34(11):1480-9
references: 17046567
references: Blood. 1998 Dec 15;92(12):4509-20
references: 9845515
references: Development. 2011 Jun;138(12):2417-27
references: 21610023
references: Blood. 1992 Oct 1;80(7):1725-35
references: 1391942
references: Leukemia. 1994 Aug;8(8):1301-8
references: 7520101
references: J Exp Med. 2006 May 15;203(5):1235-47
references: 16636132
references: J Biol Chem. 1997 Sep 12;272(37):23366-70
references: 9287350
references: J Biol Chem. 2001 Feb 9;276(6):4012-9
references: 11060298
references: Blood. 1998 Oct 15;92(8):2712-8
references: 9763554
references: Leuk Res. 2007 Oct;31(10):1403-11
references: 17445886
references: Blood. 1997 Aug 1;90(3):1014-21
references: 9242531
references: Cancer Res. 1998 Jul 15;58(14):3163-72
references: 9679985
references: Blood. 2005 Sep 1;106(5):1755-61
references: 15905186
references: Blood. 1994 Apr 1;83(7):1909-21
references: 7511442
references: EMBO J. 2003 Nov 3;22(21):5806-16
references: 14592978
references: J Cancer Res Clin Oncol. 2008 Aug;134(8):861-72
references: 18288489
references: Blood. 1985 Feb;65(2):484-91
references: 2981591
references: J Biol Chem. 2011 Sep 9;286(36):31263-71
references: 21771795
references: Oncogene. 2001 Oct 29;20(49):7140-5
references: 11704842
references: Blood. 1997 Oct 1;90(7):2591-600
references: 9326225
references: Haematologica. 2006 Aug;91(8):1017-26
references: 16870554
references: Cancer Lett. 2000 Feb 1;148(2):207-13
references: 10695998
references: Stem Cells. 2007 Jun;25(6):1384-92
references: 17332507
references: Exp Hematol. 2003 May;31(5):413-20
references: 12763140
references: N Engl J Med. 1991 May 16;324(20):1385-93
references: 1850498
references: Haematologica. 2010 Jan;95(1):47-56
references: 19713224
references: Oncogene. 1995 Dec 7;11(11):2439-44
references: 8570196
references: Ann Intern Med. 1993 Mar 15;118(6):472-3
references: 8439125
references: Lancet. 2004 May 1;363(9419):1439-41
references: 15121408
references: Blood. 1999 Aug 15;94(4):1192-200
references: 10438706
references: Blood. 2010 Dec 9;116(24):5289-97
references: 20739655
references: Mol Pain. 2012 Jan 24;8:6
references: 22273495
references: J Cell Physiol. 2011 Jul;226(7):1860-7
references: 21442622
references: Blood. 1988 Jan;71(1):242-7
references: 3422031
references: Nature. 1986 Jun 12-18;321(6071):702-6
references: 3520340
references: Blood. 1991 Mar 1;77(5):1080-6
references: 1995093
references: Blood. 2008 Mar 1;111(5):2505-15
references: 18299451
references: J Clin Oncol. 1998 Jan;16(1):78-85
references: 9440726
references: Blood. 2005 Jan 1;105(1):341-9
references: 15339853
references: Leukemia. 2009 May;23(5):925-33
references: 19148141
references: Biochem Pharmacol. 2009 Feb 1;77(3):384-96
references: 19038232
references: Cancer Res. 1993 Feb 1;53(3):472-6
references: 8381046
references: Leukemia. 2002 Oct;16(10):1940-58
references: 12357346
references: Blood. 2000 Jan 1;95(1):90-5
references: 10607690
references: Blood. 1994 Dec 1;84(11):3843-9
references: 7949141
references: Blood. 1996 Aug 15;88(4):1390-8
references: 8695858
references: Blood. 2005 Oct 1;106(7):2452-61
references: 15972450
references: Blood. 1997 May 15;89(10):3554-64
references: 9160660
references: Leukemia. 2002 Apr;16(4):683-92
references: 11960350
references: Stem Cells Dev. 2008 Jun;17(3):463-73
references: 18522494
references: Biomaterials. 2011 Oct;32(29):7023-33
references: 21705076
references: Blood. 1994 Jul 1;84(1):294-302
references: 7517212
references: Blood. 2004 Mar 1;103(5):1693-701
references: 14604978
references: Exp Hematol. 2005 Jul;33(7):828-35
references: 15963859
references: J Clin Invest. 1999 May 15;103(10):1399-408
references: 10330422
references: Blood. 1995 Jun 15;85(12):3619-35
references: 7780146
references: Exp Cell Res. 2005 Nov 1;310(2):319-30
references: 16181625
references: Exp Cell Res. 2001 Apr 1;264(2):193-200
references: 11262176
references: Biochem Biophys Res Commun. 2002 Sep 6;296(5):1125-33
references: 12207890
references: Cell Transplant. 1997 Mar-Apr;6(2):125-34
references: 9142444