The mll-AF9 gene fusion in mice controls myeloproliferation and specifies acute myeloid leukaemogenesis.
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.
MRC Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Hills Road, Cambridge, CB2 2QH, UK.
C L
CL
Dobson
A J
AJ
Warren
R
R
Pannell
A
A
Forster
I
I
Lavenir
J
J
Corral
A J
AJ
Smith
T H
TH
Rabbitts
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000473:pathology; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics; D006579:Heterozygote; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007668:Kidney / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051788:Myeloid-Lymphoid Leukemia Protein; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000235:genetics / Q000473:pathology; D011519:Proto-Oncogenes; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000473:pathology; D014157:Transcription Factors; D014178:Translocation, Genetic / Q000235:genetics
D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; C489901:MLLT3 protein, human; C489902:Mllt3 protein, mouse; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse