The MII-AF9 gene fusion in mice controls myeloproliferation and specifies acute myeloid leukaemogenesis

被引:171
作者
Dobson, CL [1 ]
Warren, AJ [1 ]
Pannell, R [1 ]
Forster, A [1 ]
Lavenir, I [1 ]
Corral, J [1 ]
Smith, AJH [1 ]
Rabbitts, TH [1 ]
机构
[1] MRC, Mol Biol Lab, Div Prot & Nucl Acid Chem, Cambridge CB2 2QH, England
关键词
ALL-1; chromosomal translocations; haematopoiesis; HRX; leukaemia;
D O I
10.1093/emboj/18.13.3564
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The MLL gene from human chromosome 11q23 is involved in >30 different chromosomal translocations resulting in a plethora of different MLL fusion proteins. Each of these tends to associate with a specific leukaemia type, for example, MLL-AF9 is found mainly in acute myeloid leukaemia. We have studied the role of the Mll-AF9 gene fusion made in mouse embryonic stem cells by an homologous recombination knock-in. Acute leukaemias developed in heterozygous mice carrying this fusion as well as in chimeric mice. As with human chromosomal translocation t(9;11), the majority of cases were acute myeloid leukaemias (AMLs) involving immature myeloblasts, but a minority were acute lymphoblastic leukaemia. The AMLs were preceded by effects on haematopoietic differentiation involving a myeloproliferation resulting in accumulation of Mac-1/Gr-1 double-positive mature myeloid cells in bone marrow as early as 6 days after birth. Therefore, non-malignant expansion of myeloid precursors is the first stage of Mll-AF9-mediated leukaemia followed by accumulation of malignant cells in bone marrow and other tissues. Thus, the late onset of overt tumours suggests that secondary tumorigenic mutations are necessary for malignancy associated with MLL-AF9 gene fusion and that myeloproliferation provides the pool of cells in which such events can occur.
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页码:3564 / 3574
页数:11
相关论文
共 59 条
[31]  
MORRISSEY J, 1993, BLOOD, V81, P1124
[32]   GENES ON CHROMOSOME-4, CHROMOSOME-9, AND CHROMOSOME-19 INVOLVED IN 11Q23 ABNORMALITIES IN ACUTE-LEUKEMIA SHARE SEQUENCE HOMOLOGY AND OR COMMON MOTIFS [J].
NAKAMURA, T ;
ALDER, H ;
GU, Y ;
PRASAD, R ;
CANAANI, O ;
KAMADA, N ;
GALE, RP ;
LANGE, B ;
CRIST, WM ;
NOWELL, PC ;
CROCE, CM ;
CANAANI, E .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (10) :4631-4635
[33]   Translocation t(4;11)(q21;q23) and MLL gene rearrangement in acute lymphoblastic leukemia secondary to anti topoisomerase II anticancer agents [J].
Nasr, F ;
MacIntyre, E ;
Venuat, AM ;
Bayle, C ;
Carde, P ;
Ribrag, V .
LEUKEMIA & LYMPHOMA, 1997, 25 (3-4) :399-401
[34]   CONSTRUCTION OF NOVEL ANTIBODIES BY USE OF DNA TRANSFECTION - DESIGN OF PLASMID VECTORS [J].
NEUBERGER, MS ;
WILLIAMS, GT .
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES, 1986, 317 (1540) :425-432
[35]  
NOWELL PC, 1960, SCIENCE, V132, P1497
[36]   FUSION OF THE FUS GENE WITH ERG IN ACUTE MYELOID-LEUKEMIA WITH T(16-21)(P11-Q22) [J].
PANAGOPOULOS, I ;
AMAN, P ;
FIORETOS, T ;
HOGLUND, M ;
JOHANSSON, B ;
MANDAHL, N ;
HEIM, S ;
BEHRENDTZ, M ;
MITELMAN, F .
GENES CHROMOSOMES & CANCER, 1994, 11 (04) :256-262
[37]  
Panagopoulos I, 1996, ONCOGENE, V12, P489
[38]  
Papaioannou V., 1993, Gene targeting: a practical approach., P107
[39]   SECONDARY ACUTE MYELOID-LEUKEMIA IN CHILDREN TREATED FOR ACUTE LYMPHOID LEUKEMIA [J].
PUI, CH ;
BEHM, FG ;
RAIMONDI, SC ;
DODGE, RK ;
GEORGE, SL ;
RIVERA, GK ;
MIRRO, J ;
KALWINSKY, DK ;
DAHL, GV ;
MURPHY, SB ;
CRIST, WM ;
WILLIAMS, DL .
NEW ENGLAND JOURNAL OF MEDICINE, 1989, 321 (03) :136-142
[40]   FUSION OF THE DOMINANT-NEGATIVE TRANSCRIPTION REGULATOR CHOP WITH A NOVEL GENE FUS BY TRANSLOCATION T(12-16) IN MALIGNANT LIPOSARCOMA [J].
RABBITTS, TH ;
FORSTER, A ;
LARSON, R ;
NATHAN, P .
NATURE GENETICS, 1993, 4 (02) :175-180