title: AML1-ETO fusion protein up-regulates TRKA mRNA expression in human CD34+ cells, allowing nerve growth factor-induced expansion.
abstract: The AML1-ETO fusion protein, generated by the t(8;21) in acute myeloid leukemia (AML), exerts dominant-negative functions and a variety of gains of function, including a positive effect on the growth of primary human CD34+ hematopoietic stem/progenitor cells. We now show that AML1-ETO expression up-regulates the level of TRKA mRNA and protein in these cells and that AML1-ETO-expressing CD34+ hematopoietic cells grown in the presence of five early-acting hematopoietic cytokines further proliferate in response to nerve growth factor (NGF). These cells also show a unique response to NGF and IL-3; namely, they expand in liquid culture. To determine the biological relevance of our findings, we analyzed 262 primary AML patient samples using real-time RT-PCR and found that t(8;21)-positive AML samples express significantly higher levels of TRKA mRNA than other subtypes of AML. NGF, which is normally expressed by bone marrow stromal cells, could provide important proliferative or survival signals to AML1-ETO-expressing leukemic or preleukemic cells, and the NGF/TRKA signaling pathway may be a suitable target for therapeutic approaches to AML.
authors.affiliation: Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
authors.forename: Vladimir
authors.initials: V
authors.lastname: Jankovic
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.forename: Jorg
authors.initials: J
authors.lastname: Cammenga
authors.forename: Ondrej
authors.initials: O
authors.lastname: Krejci
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Bob
authors.initials: B
authors.lastname: Lowenberg
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
mesh_terms: D018952:Antigens, CD34 / Q000276:immunology*; D002455:Cell Division / Q000502:physiology; D050676:Core Binding Factor Alpha 2 Subunit; D005786:Gene Expression Regulation / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D020917:Receptor, trkA / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic; D015854:Up-Regulation
chemical_list: C107844:AML1-ETO fusion protein, human; D018952:Antigens, CD34; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors; D020932:Nerve Growth Factor; D020917:Receptor, trkA
references.citation: Cell. 1996 Jan 26;84(2):321-30
references.pmid: 8565077
references.citation: Blood. 2004 Mar 15;103(6):2316-24
references.pmid: 14615365
references.citation: Blood. 1996 Sep 1;88(5):1608-18
references.pmid: 8781416
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11895-900
references.pmid: 8876234
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12359-63
references.pmid: 8901586
references.citation: Cell. 1996 Nov 15;87(4):697-708
references.pmid: 8929538
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14059-64
references.pmid: 8943060
references.citation: J Androl. 1996 Sep-Oct;17(5):481-90
references.pmid: 8957691
references.citation: Proc Natl Acad Sci U S A. 1997 May 27;94(11):5697-702
references.pmid: 9159135
references.citation: Blood. 1998 May 1;91(9):3134-43
references.pmid: 9558367
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10860-5
references.pmid: 9724795
references.citation: Mol Cell Biol. 1998 Dec;18(12):7176-84
references.pmid: 9819404
references.citation: Mol Cell Biol. 1998 Dec;18(12):7185-91
references.pmid: 9819405
references.citation: Blood. 1999 Feb 15;93(4):1355-63
references.pmid: 9949179
references.citation: Am J Pathol. 1999 Feb;154(2):405-15
references.pmid: 10027399
references.citation: Blood. 1999 Mar 15;93(6):1817-24
references.pmid: 10068652
references.citation: Oncogene. 1999 Mar 4;18(9):1701-10
references.pmid: 10208431
references.citation: Nat Genet. 1999 Oct;23(2):166-75
references.pmid: 10508512
references.citation: J Biol Chem. 2000 Jan 7;275(1):651-6
references.pmid: 10617663
references.citation: Mol Cell Biol. 2000 Mar;20(6):2075-86
references.pmid: 10688654
references.citation: EMBO J. 2000 Apr 17;19(8):1827-38
references.pmid: 10775267
references.citation: Blood. 2000 Jul 15;96(2):655-63
references.pmid: 10887131
references.citation: Blood. 2000 Sep 15;96(6):2108-15
references.pmid: 10979955
references.citation: Blood. 2000 Oct 15;96(8):2862-9
references.pmid: 11023523
references.citation: Mol Cell Biol. 2000 Dec;20(23):8655-66
references.pmid: 11073967
references.citation: Semin Cell Dev Biol. 2000 Oct;11(5):347-60
references.pmid: 11105899
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
references.pmid: 11309499
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10398-403
references.pmid: 11526243
references.citation: Curr Opin Hematol. 2001 Jul;8(4):192-6
references.pmid: 11561154
references.citation: Blood. 2002 Jan 1;99(1):15-23
references.pmid: 11756147
references.citation: Science. 2002 Apr 19;296(5567):497
references.pmid: 11964471
references.citation: Oncogene. 2002 May 13;21(21):3422-44
references.pmid: 12032780
references.citation: Cancer Cell. 2002 Feb;1(1):63-74
references.pmid: 12086889
references.citation: Nat Med. 2002 Jul;8(7):743-50
references.pmid: 12091906
references.citation: Mol Cell Biol. 2002 Aug;22(15):5506-17
references.pmid: 12101243
references.citation: J Exp Med. 2002 Nov 4;196(9):1227-40
references.pmid: 12417632
references.citation: Cell. 2002 Nov 27;111(5):621-33
references.pmid: 12464175
references.citation: Mol Cell Biol. 2004 Apr;24(7):2890-904
references.pmid: 15024077
references.citation: N Engl J Med. 2004 Apr 15;350(16):1617-28
references.pmid: 15084694
references.citation: EMBO J. 1993 Jul;12(7):2715-21
references.pmid: 8334990
references.citation: Blood. 1993 Aug 1;82(3):712-5
references.pmid: 8338940
references.citation: Blood. 1994 Mar 15;83(6):1479-85
references.pmid: 8123839
references.citation: Mol Cell Biol. 1995 Apr;15(4):1974-82
references.pmid: 7891692
references.citation: Oncogene. 1995 Dec 21;11(12):2667-74
references.pmid: 8545124
references.citation: Blood. 2003 Jan 15;101(2):673-80
references.pmid: 12393679
references.citation: Blood. 2003 Mar 15;101(6):2206-14
references.pmid: 12406909
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9506-11
references.pmid: 12881486
references.citation: Front Biosci. 2003 Sep 1;8:s1181-6
references.pmid: 12957860
references.citation: Blood. 2003 Dec 15;102(13):4369-76
references.pmid: 12946995
references.citation: J Clin Invest. 2003 Dec;112(11):1751-61
references.pmid: 14660751
references.citation: Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3444-9
references.pmid: 8622955