Development of a multi-step leukemogenesis model of mll-rearranged leukemia using humanized mice

Kunihiko Moriya, Makiko Suzuki, Yohei Watanabe, Takeshi Takahashi, Yoko Aoki, Toru Uchiyama, Satoru Kumaki, Yoji Sasahara, Masayoshi Minegishi, Shigeo Kure, Shigeru Tsuchiya, Kazuo Sugamura, Naoto Ishii

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

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.

Original languageEnglish
Article numbere37892
JournalPloS one
Volume7
Issue number6
DOIs
Publication statusPublished - 2012 Jun 20

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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