Abstract
Mixed-lineage-leukemia (MLL) fusion oncogenes are intimately involved in acute leukemia and secondary therapy-related acute leukemia. To understand MLL-rearranged leukemia, several murine models for this disease have been established. However, the mouse leukemia derived from mouse hematopoietic stem cells (HSCs) may not be fully comparable with human leukemia. Here we developed a humanized mouse model for human leukemia by transplanting human cord blood-derived HSCs transduced with an MLL-AF10 oncogene into a supra-immunodeficient mouse strain, NOD/Shi-scid, IL-2Rγ−/− (NOG) mice. Injection of the MLL-AF10-transduced HSCs into the liver of NOG mice enhanced multilineage hematopoiesis, but did not induce leukemia. Because active mutations in ras genes are often found in MLL-related leukemia, we next transduced the gene for a constitutively active form of K-ras along with the MLL-AF10 oncogene. Eight weeks after transplantation, all the recipient mice had developed acute monoblastic leukemia (the M5 phenotype in French-American-British classification). We thus successfully established a human MLL-rearranged leukemia that was derived in vivo from human HSCs. In addition, since the enforced expression of the mutant K-ras alone was insufficient to induce leukemia, the present model may also be a useful experimental platform for the multi-step leukemogenesis model of human leukemia.
Highlights
Chromosomal translocations that result in MLL-fusion oncogenes are associated with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome, and secondary therapy-related acute leukemia [1]
A detailed understanding of leukemogenesis requires the development of experimental murine models that can accurately mimic this process
The leukemia occurring in mice often does not faithfully recapitulate human leukemia, in part because of the biological differences between human and mouse hematopoietic stem cells (HSCs) [8,27]
Summary
Chromosomal translocations that result in MLL (mixed-lineage leukemia)-fusion oncogenes are associated with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome, and secondary therapy-related acute leukemia [1]. More than 60 partner genes that form MLL-fusion oncogenes have been identified [2], and the partner usually characterizes the specific pathological phenotype of the MLL-rearranged leukemia. To gain insight into the etiology and pathogenesis of MLLrearranged leukemia, several mouse models have been developed. Mice with a knocked-in MLL-AF9 fusion gene develop AML as they age [5], in humans the congenital MLL-AF9 rearrange typically affects infants. The phenotype and pathogenesis of the leukemia produced in these murine models sometimes do not match those observed in human leukemia associated with the same genetic lesion. The MLL-ENL fusion gene is frequently associated with B-precursor ALL in humans, but generates AML in mice [7]. There is a gap in our understanding about mouse versus human leukemogenesis, and further leukemia modeling studies using human primary leukemia cells are needed [8]
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