title: IGF-IR determines the fates of BCR/ABL leukemia.
abstract: BACKGROUND
  The tyrosine kinase receptor insulin-like growth factor 1 receptor (IGF-IR) contributes to the initiation and progression of many types of malignancies. We previously showed that IGF-2, which binds IGF-IR, is an extrinsic factor that supports the ex vivo expansion of hematopoietic stem cells (HSCs). We also demonstrated that IGF-IR is not required for HSC activity in vivo.
  
  
  RESULTS
  Here we investigated the role of IGF-IR in chronic myeloid leukemia (CML) using the retroviral BCR/ABL transplantation mouse model. Existing antibodies against IGF-IR are not suitable for flow cytometry; therefore, we generated a fusion of the human IgG Fc fragment with mutant IGF-2 that can bind to IGF-IR. We used this fusion protein to evaluate mouse primary hematopoietic populations. Through transplantation assays with IGF-IR(+) and IGF-IR(-) cells, we demonstrated that IGF-IR is expressed on all mouse HSCs. The expression of IGF-IR is much higher on CML cells than on acute lymphoblastic leukemia (ALL) cells. The depletion of IGF-IR expression in BCR/ABL(+) cells led to the development of ALL (mostly T cell ALL) but not CML. Lack of IGF-IR resulted in decreased self-renewal of the BCR/ABL(+) CML cells in the serial replating assay.
  
  
  CONCLUSIONS
  IGF-IR regulates the cell fate determination of BCR/ABL(+) leukemia cells and supports the self-renewal of CML cells.
authors: Taishan Scholar Immunology Program, Binzhou Medical University, 264003, Yantai, Shandong, China. jjx.cau@139.com.
authors: Jingjing
authors: J
authors: Xie
authors: Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, 75390, Dallas, TX, USA. xiaoli.chen@utsouthwestern.edu.
authors: Xiaoli
authors: X
authors: Chen
authors: Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, 75390, Dallas, TX, USA. junke.zheng@utsouthwestern.edu.
authors: Junke
authors: J
authors: Zheng
authors: Taishan Scholar Immunology Program, Binzhou Medical University, 264003, Yantai, Shandong, China. bzyxylcl@163.com.
authors: Chunling
authors: C
authors: Li
authors: Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, 75390, Dallas, TX, USA. satomi.stacy@utsouthwestern.edu.
authors: Satomi
authors: S
authors: Stacy
authors: INSERM and Sorbonne Universities, UPMC, Research Center UMR938, 75012, Paris, France. martin.holzenberger@inserm.fr.
authors: Martin
authors: M
authors: Holzenberger
authors: Taishan Scholar Immunology Program, Binzhou Medical University, 264003, Yantai, Shandong, China. xue-mei-hu@163.com.
authors: Xuemei
authors: X
authors: Hu
authors: Taishan Scholar Immunology Program, Binzhou Medical University, 264003, Yantai, Shandong, China. alec.zhang@utsouthwestern.edu.|Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, 75390, Dallas, TX, USA. alec.zhang@utsouthwestern.edu.
authors: Cheng Cheng
authors: CC
authors: Zhang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D017526:Receptor, IGF Type 1; D016044:Fusion Proteins, bcr-abl
references: J Hematol Oncol. 2013;6(1):72
references: 24191913
references: Nature. 1985 Jun 13-19;315(6020):550-4
references: 2989692
references: Blood. 2014 Apr 17;123(16):2443-5
references: 24744248
references: Exp Hematol. 2012 Sep;40(9):715-723.e6
references: 22613471
references: Blood. 2014 Apr 17;123(16):2540-9
references: 24574458
references: Leukemia. 2007 Sep;21(9):1921-30
references: 17581609
references: Science. 1990 Feb 16;247(4944):824-30
references: 2406902
references: Blood. 2012 Dec 13;120(25):4963-72
references: 22995899
references: Blood. 2011 Sep 22;118(12):3236-43
references: 21821709
references: Blood. 2005 Sep 15;106(6):2128-37
references: 15914554
references: Stem Cells. 2008 Jun;26(6):1628-35
references: 18369099
references: J Clin Invest. 2011 Jan;121(1):396-409
references: 21157039
references: Science. 2004 Oct 8;306(5694):269-71
references: 15472075
references: Cell Stem Cell. 2011 Aug 5;9(2):119-30
references: 21816363
references: Leukemia. 2002 Nov;16(11):2190-6
references: 12399961
references: Blood. 2007 Oct 1;110(7):2242-9
references: 17496200
references: Cancer Lett. 2003 Jun 10;195(2):127-37
references: 12767520
references: J Exp Med. 1999 May 3;189(9):1399-412
references: 10224280
references: Blood. 2014 Aug 7;124(6):924-35
references: 24899623
references: Nat Rev Cancer. 2012 Aug;12(8):513-26
references: 22825216
references: Cancer Cell. 2004 Mar;5(3):221-30
references: 15050914
references: Cell. 1993 Oct 8;75(1):73-82
references: 8402902
references: Leuk Res. 2012 Jul;36(7):905-11
references: 22424712
references: Nat Med. 2006 Oct;12(10):1175-80
references: 16998483
references: Cell. 1984 Jul;37(3):1035-42
references: 6204766
references: J Biol Chem. 1991 Nov 5;266(31):20626-35
references: 1657932
references: Blood. 2014 Feb 13;123(7):992-1001
references: 24385538
references: Blood. 2004 Apr 1;103(7):2513-21
references: 14592820
references: Nature. 2003 Jan 9;421(6919):182-7
references: 12483226
references: Nature. 2012 May 31;485(7400):656-60
references: 22660330
references: Science. 2001 Aug 3;293(5531):876-80
references: 11423618
references: Blood. 1998 Nov 15;92(10):3829-40
references: 9808576
references: Leuk Res Treatment. 2012;2012:671702
references: 23259070
references: Cancer Lett. 2013 Sep 10;338(1):15-22
references: 22906415
references: Nature. 2007 Aug 30;448(7157):1015-21
references: 17625568
references: Nat Rev Cancer. 2004 Jul;4(7):505-18
references: 15229476
references: Blood. 2014 Feb 27;123(9):1361-71
references: 24394666
references: Endocr Rev. 2000 Jun;21(3):215-44
references: 10857553
references: Blood. 2013 Nov 28;122(23):3767-77
references: 24100446
references: Cancer Cell. 2011 Nov 15;20(5):661-73
references: 22094259
references: Oncogene. 2008 Jun 19;27(27):3831-44
references: 18246120