Dissection of the transformation of primary human hematopoietic cells by the oncogene NUP98-HOXA9.
NUP98-HOXA9 is the prototype of a group of oncoproteins associated with acute myeloid leukemia. It consists of an N-terminal portion of NUP98 fused to the homeodomain of HOXA9 and is believed to act as an aberrant transcription factor that binds DNA through the homeodomain. Here we show that NUP98-HOXA9 can regulate transcription without binding to DNA. In order to determine the relative contributions of the NUP98 and HOXA9 portions to the transforming ability of NUP98-HOXA9, the effects of NUP98-HOXA9 on primary human CD34+ cells were dissected and compared to those of wild-type HOXA9. In contrast to previous findings in mouse cells, HOXA9 had only mild effects on the differentiation and proliferation of primary human hematopoietic cells. The ability of NUP98-HOXA9 to disrupt the differentiation of primary human CD34+ cells was found to depend primarily on the NUP98 portion, whereas induction of long-term proliferation required both the NUP98 moiety and an intact homeodomain. Using oligonucleotide microarrays in primary human CD34+ cells, a group of genes was identified whose dysregulation by NUP98-HOXA9 is attributable primarily to the NUP98 portion. These include RAP1A, HEY1, and PTGS2 (COX-2). Their functions may reflect the contribution of the NUP98 moiety of NUP98-HOXA9 to leukemic transformation. Taken together, these results suggest that the effects of NUP98-HOXA9 on gene transcription and cell transformation are mediated by at least two distinct mechanisms: one that involves promoter binding through the homeodomain with direct transcriptional activation, and another that depends predominantly on the NUP98 moiety and does not involve direct DNA binding.
Yassin
Enas R
ER
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Sarma
Nayan J
NJ
Abdul-Nabi
Anmaar M
AM
Dombrowski
James
J
Han
Ye
Y
Takeda
Akiko
A
Yaseen
Nabeel R
NR
D000595:Amino Acid Sequence; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology*; D002471:Cell Transformation, Neoplastic; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000502:physiology; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D008969:Molecular Sequence Data; D028861:Nuclear Pore Complex Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D009857:Oncogenes; D014158:Transcription, Genetic / Q000502:physiology
D017931:DNA Primers; D018398:Homeodomain Proteins; D028861:Nuclear Pore Complex Proteins; C465451:Nup98 protein, human; C097899:homeobox protein HOXA9
Exp Hematol. 2005 Jul;33(7):719-37
15963848
Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1769-73
7878057
J Biol Chem. 2004 Jan 9;279(2):866-75
14561764
EMBO J. 2004 Mar 10;23(5):1155-65
14976548
Mol Cell Biol. 2000 May;20(9):3274-85
10757811
Oncogene. 2007 Oct 15;26(47):6766-76
17934484
J Cell Mol Med. 2009 Jan;13(1):136-46
18363832
Blood. 2008 Jun 15;111(12):5672-82
18388181
Leukemia. 2006 Apr;20(4):696-706
16467868
Blood. 2005 Nov 1;106(9):2952-61
16076873
Cell. 1989 Jan 13;56(1):77-84
2642744
Cancer Res. 2006 Jul 1;66(13):6628-37
16818636
Int J Cancer. 2005 Apr 20;114(4):634-8
15609330
J Pathol. 2009 Jun;218(2):201-9
19235837
J Biol Chem. 2000 Oct 6;275(40):31289-96
10875935
J Biol Chem. 1997 Mar 28;272(13):8198-206
9079637
PLoS One. 2007 Aug 22;2(8):e768
17712416
Leukemia. 2002 Feb;16(2):186-95
11840284
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2450-5
12604785
Drug Resist Updat. 2008 Dec;11(6):210-8
18951834
Cancer Res. 2006 Dec 15;66(24):11781-91
17178874
Exp Hematol. 2007 Sep;35(9):1321-32
17637499
Leukemia. 1999 Dec;13(12):1993-9
10602420
J Biol Chem. 2005 Apr 1;280(13):12359-70
15681849
Nat Rev Cancer. 2006 Feb;6(2):130-40
16491072
Annu Rev Biochem. 1994;63:487-526
7979246
Blood. 1999 Jul 15;94(2):741-7
10397741
Cell. 1994 Jul 29;78(2):211-23
8044836
Oncogene. 2008 Oct 9;27(46):6056-67
18604245
J Cell Physiol. 2003 Mar;194(3):237-55
12548545
Oncogene. 2002 Jun 20;21(27):4247-56
12082612
Mol Cell Proteomics. 2007 Feb;6(2):272-82
17079785
Subcell Biochem. 2007;42:93-126
17612047
Nat Genet. 1996 Feb;12(2):159-67
8563754
Oncogene. 1992 Feb;7(2):323-9
1549353
J Biol Chem. 2001 Mar 30;276(13):10453-62
11124936
J Cell Biol. 1999 Apr 19;145(2):237-54
10209021
Curr Pharm Des. 2008;14(21):2051-60
18691115
Mol Cell Biol. 2001 Apr;21(8):2659-70
11283246
Blood. 2003 Mar 1;101(5):1744-51
12393469
Leuk Lymphoma. 2008 Aug;49(8):1452-62
18608871
EMBO J. 2001 Feb 1;20(3):350-61
11157742
Nat Cell Biol. 2007 Jul;9(7):804-12
17589499
Oncogene. 2005 Sep 22;24(42):6418-31
16007190
Biochem Biophys Res Commun. 2000 Aug 28;275(2):652-60
10964718
Cancer Res. 2006 May 1;66(9):4584-90
16651408
Nat Genet. 1996 Feb;12(2):154-8
8563753
Mol Cell Biol. 2004 Sep;24(17):7779-94
15314183
Exp Cell Res. 2004 Oct 15;300(1):84-93
15383317
Mol Cell Biol. 1999 Nov;19(11):7577-88
10523646
Proc Natl Acad Sci U S A. 1990 May;87(9):3584-8
2333304
Mol Cell Biol. 1999 Jan;19(1):764-76
9858599
Blood. 2003 Jun 1;101(11):4529-38
12543865
Blood. 2004 Aug 15;104(4):1127-36
15100157
N Engl J Med. 2004 Apr 15;350(16):1605-16
15084693
Biochem Biophys Res Commun. 2008 Aug 8;372(4):629-33
18503747
Trends Biochem Sci. 2003 May;28(5):267-75
12765839
Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4451-6
9114010
Cancer Res. 2007 Sep 1;67(17):8051-7
17804716
Hum Mol Genet. 2009 Apr 15;18(8):1464-70
19228774
Leukemia. 1999 May;13(5):687-98
10374871