title: Development of a multi-step leukemogenesis model of MLL-rearranged leukemia using humanized mice.
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.
authors: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Kunihiko
authors: K
authors: Moriya
authors: Makiko
authors: M
authors: Suzuki
authors: Yohei
authors: Y
authors: Watanabe
authors: Takeshi
authors: T
authors: Takahashi
authors: Yoko
authors: Y
authors: Aoki
authors: Toru
authors: T
authors: Uchiyama
authors: Satoru
authors: S
authors: Kumaki
authors: Yoji
authors: Y
authors: Sasahara
authors: Masayoshi
authors: M
authors: Minegishi
authors: Shigeo
authors: S
authors: Kure
authors: Shigeru
authors: S
authors: Tsuchiya
authors: Kazuo
authors: K
authors: Sugamura
authors: Naoto
authors: N
authors: Ishii
mesh_terms: D000818:Animals; D015139:Blotting, Southern; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C092513:MLLT10 protein, human; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein