title: A specific need for CRKL in p210BCR-ABL-induced transformation of mouse hematopoietic progenitors.
abstract: CRKL (CRK-like) is an adapter protein predominantly phosphorylated in cells that express the tyrosine kinase p210(BCR-ABL), the fusion product of a (9;22) chromosomal translocation causative for chronic myeloid leukemia. It has been unclear, however, whether CRKL plays a functional role in p210(BCR-ABL) transformation. Here, we show that CRKL is required for p210(BCR-ABL) to support interleukin-3-independent growth of myeloid progenitor cells and long-term outgrowth of B-lymphoid cells from fetal liver-derived hematopoietic progenitor cells. Furthermore, a synthetic phosphotyrosyl peptide that binds to the CRKL SH2 domain with high affinity blocks association of endogenous CRKL with the p210(BCR-ABL) complex and reduces c-MYC levels in K562 human leukemic cells as well as in mouse hematopoietic cells transformed by p210(BCR-ABL) or the imatinib-resistant mutant T315I. These results indicate that the function of CRKL as an adapter protein is essential for p210(BCR-ABL)-induced transformation.
authors.affiliation: Ben May Department for Cancer Research, Committees on Developmental Biology, Genetics, Cancer Biology, and Cell Physiology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ji-Heui
authors.initials: JH
authors.lastname: Seo
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Wood
authors.forename: Anupriya
authors.initials: A
authors.lastname: Agarwal
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Hare
authors.forename: Collin R
authors.initials: CR
authors.lastname: Elsea
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Griswold
authors.forename: Michael W N
authors.initials: MW
authors.lastname: Deininger
authors.forename: Akira
authors.initials: A
authors.lastname: Imamoto
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D020014:K562 Cells; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D007377:Interleukin-3; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D050799:STAT5 Transcription Factor; D051020:bcl-X Protein; D016044:Fusion Proteins, bcr-abl
references.citation: Blood. 1994 Sep 15;84(6):1731-6
references.pmid: 7521685
references.citation: Nat Genet. 2002 Sep;32(1):201-5
references.pmid: 12161751
references.citation: Blood. 2000 Sep 15;96(6):2277-83
references.pmid: 10979977
references.citation: FASEB J. 2000 Aug;14(11):1529-38
references.pmid: 10928987
references.citation: J Immunol. 2000 Mar 1;164(5):2533-41
references.pmid: 10679091
references.citation: Blood. 2000 Sep 15;96(6):2269-76
references.pmid: 10979976
references.citation: Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8392-6
references.pmid: 7690960
references.citation: Nat Rev Cancer. 2002 Oct;2(10):764-76
references.pmid: 12360279
references.citation: Mol Cell Biol. 1988 Oct;8(10):4079-87
references.pmid: 3263566
references.citation: Nat Rev Drug Discov. 2007 Oct;6(10):834-48
references.pmid: 17853901
references.citation: Science. 1990 Mar 2;247(4946):1079-82
references.pmid: 2408149
references.citation: Mol Cell Biol. 1997 Nov;17(11):6708-16
references.pmid: 9343435
references.citation: Proc Natl Acad Sci U S A. 1990 Sep;87(17):6649-53
references.pmid: 2204061
references.citation: Cancer Res. 2002 Jan 15;62(2):535-41
references.pmid: 11809706
references.citation: Eur J Immunol. 2003 Oct;33(10):2687-95
references.pmid: 14515252
references.citation: Proc Natl Acad Sci U S A. 1990 Mar;87(5):1908-12
references.pmid: 2408044
references.citation: Proc Natl Acad Sci U S A. 1987 Sep;84(18):6558-62
references.pmid: 3498165
references.citation: Oncogene. 2002 May 9;21(20):3225-31
references.pmid: 12082638
references.citation: Science. 1990 Feb 16;247(4944):824-30
references.pmid: 2406902
references.citation: Curr Top Microbiol Immunol. 1992;182:65-72
references.pmid: 1490392
references.citation: Blood. 1994 Nov 1;84(9):2912-8
references.pmid: 7524758
references.citation: Oncogene. 2002 Dec 12;21(57):8804-16
references.pmid: 12483533
references.citation: Proc Natl Acad Sci U S A. 1988 Dec;85(23):9312-6
references.pmid: 3143116
references.citation: Nat Struct Mol Biol. 2007 Jun;14(6):503-10
references.pmid: 17515907
references.citation: Oncogene. 1997 Feb 6;14(5):507-13
references.pmid: 9053848
references.citation: Cancer Res. 2001 Feb 15;61(4):1398-405
references.pmid: 11245441
references.citation: Oncogene. 2001 Oct 1;20(44):6348-71
references.pmid: 11607838
references.citation: Science. 1994 Apr 15;264(5157):424-6
references.pmid: 8153630
references.citation: Nature. 1983 Nov 17-23;306(5940):277-80
references.pmid: 6580527
references.citation: Hum Gene Ther. 1994 Jan;5(1):19-28
references.pmid: 8155767
references.citation: Nat Biotechnol. 2001 Dec;19(12):1173-6
references.pmid: 11731788
references.citation: Nat Genet. 2001 Mar;27(3):293-8
references.pmid: 11242111
references.citation: Exp Hematol. 2000 Mar;28(3):305-10
references.pmid: 10720695
references.citation: EMBO J. 1990 Apr;9(4):1069-78
references.pmid: 1691092
references.citation: N Engl J Med. 1988 Oct 13;319(15):990-8
references.pmid: 3047582
references.citation: Nature. 1983 Nov 17-23;306(5940):239-42
references.pmid: 6316147
references.citation: Mol Cell Biol. 1998 Sep;18(9):5082-90
references.pmid: 9710592
references.citation: Dev Cell. 2006 Jan;10(1):71-80
references.pmid: 16399079
references.citation: Cell. 1992 Sep 18;70(6):901-10
references.pmid: 1525828
references.citation: Blood. 2000 Mar 15;95(6):2118-25
references.pmid: 10706883
references.citation: Oncogene. 1998 Apr 16;16(15):1903-12
references.pmid: 9591773
references.citation: Mol Cell Biol. 2009 Jun;29(11):3076-87
references.pmid: 19307307
references.citation: Oncogene. 1996 Jul 18;13(2):247-54
references.pmid: 8710363
references.citation: Blood. 1998 Nov 15;92(10):3829-40
references.pmid: 9808576
references.citation: Blood. 1996 Dec 1;88(11):4304-13
references.pmid: 8943867
references.citation: Oncogene Res. 1988;3(4):387-99
references.pmid: 3147434
references.citation: Cancer Res. 2006 May 15;66(10):5387-93
references.pmid: 16707466
references.citation: Blood. 1997 Jan 1;89(1):297-306
references.pmid: 8978305
references.citation: N Engl J Med. 2001 Apr 5;344(14):1031-7
references.pmid: 11287972
references.citation: Science. 1992 May 8;256(5058):836-9
references.pmid: 1375394
references.citation: Blood. 2002 Sep 15;100(6):1965-71
references.pmid: 12200353