Hoxa9 influences the phenotype but not the incidence of Mll-AF9 fusion gene leukemia

被引:105
作者
Kumar, AR
Hudson, WA
Chen, W
Nishiuchi, R
Yao, Q
Kersey, JH
机构
[1] Univ Minnesota, Canc Ctr, Minneapolis, MN 55455 USA
[2] Univ Minnesota, Dept Pediat, Div Hematol Oncol Blood & Marrow Transplantat, Minneapolis, MN 55455 USA
关键词
D O I
10.1182/blood-2003-07-2582
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Identification of the targets of mixed lineageleukemia (MLL) fusion genes will assist in understanding the biology of MLL fusion gene leukemias and in development of better therapies. Numerous studies have implicated HOXA9 as one of the possible targets of MLL fusion proteins. To determine if HOXA9 was required for leukemia development by MLL fusion genes, we compared the effects of the Mll-AF9 knock-in mutation in mice in the presence or absence of Hoxa9. Both groups of mice showed myeloid expansion at 8 weeks and then developed myeloid leukemia with a similar incidence and time course. The leukemia in the mice lacking Hoxa9 generally displayed a more immature myeloid phenotype than that in the mice that were wild-type for Hoxa9. Gene expression profiling revealed that expression of Mll-AF9 led to overexpression of Hoxa5, Hoxa6, Hoxa7, Hoxa9, and Hoxa10. Thus, genes of the Hox-a cluster are important in defining the phenotype but not the incidence of Mll-AF9 leukemia. These results demonstrate that the Mll-AF9 fusion gene disrupts the expression of several Hox genes, none of which as a single gene is likely to be necessary for development of leukemia. Instead, we propose that the "Hox code" minimally defined by the Hoxa5-a9 cluster is central to MLL leukemogenesis. (C) 2004 by The American Society of Hematology.
引用
收藏
页码:1823 / 1828
页数:6
相关论文
共 26 条
[1]   MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia [J].
Armstrong, SA ;
Staunton, JE ;
Silverman, LB ;
Pieters, R ;
de Boer, ML ;
Minden, MD ;
Sallan, SE ;
Lander, ES ;
Golub, TR ;
Korsmeyer, SJ .
NATURE GENETICS, 2002, 30 (01) :41-47
[2]   Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9 [J].
Ayton, PM ;
Cleary, ML .
GENES & DEVELOPMENT, 2003, 17 (18) :2298-2307
[3]   Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins [J].
Ayton, PM ;
Cleary, ML .
ONCOGENE, 2001, 20 (40) :5695-5707
[4]   Hoxa9 immortalizes a granulocyte-macrophage colony-stimulating factor-dependent promyelocyte capable of biphenotypic differentiation to neutrophils or macrophages, independent of enforced Meis expression [J].
Calvo, KR ;
Sykes, DB ;
Pasillas, M ;
Kamps, MP .
MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (09) :3274-3285
[5]   Targeted mutations in Hoxa-9 and Hoxb-9 reveal synergistic interactions [J].
Chen, F ;
Capecchi, MR .
DEVELOPMENTAL BIOLOGY, 1997, 181 (02) :186-196
[6]   Paralogous mouse Hox genes, Hoxa9, Hoxb9, and Hoxd9, function together to control development of the mammary gland in response to pregnancy [J].
Chen, F ;
Capecchi, MR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (02) :541-546
[7]   Homeobox genes in normal and malignant cells [J].
Cillo, C ;
Cantile, M ;
Faiella, A ;
Boncinelli, E .
JOURNAL OF CELLULAR PHYSIOLOGY, 2001, 188 (02) :161-169
[8]   An MII-AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: A method to create fusion oncogenes [J].
Corral, J ;
Lavenir, I ;
Impey, H ;
Warren, AJ ;
Forster, A ;
Larson, TA ;
Bell, S ;
McKenzie, ANJ ;
King, G ;
Rabbitts, TH .
CELL, 1996, 85 (06) :853-861
[9]  
Davis AP, 1996, DEVELOPMENT, V122, P1175
[10]   The MII-AF9 gene fusion in mice controls myeloproliferation and specifies acute myeloid leukaemogenesis [J].
Dobson, CL ;
Warren, AJ ;
Pannell, R ;
Forster, A ;
Lavenir, I ;
Corral, J ;
Smith, AJH ;
Rabbitts, TH .
EMBO JOURNAL, 1999, 18 (13) :3564-3574