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Blood, 15 April 2008, Vol. 111, No. 8, pp. 4297-4308.
Prepublished online as a Blood First Edition Paper on January 11, 2008; DOI 10.1182/blood-2007-01-068346.
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Submitted January 16, 2007
Accepted December 24, 2007
AML1 mutations induced MDS and MDS/AML in a mouse BMT model
Naoko Watanabe-Okochi, Jiro Kitaura, Ryoichi Ono, Hironori Harada, Yuka Harada, Yukiko Komeno, Hideaki Nakajima, Tetsuya Nosaka, Toshiya Inaba, and Toshio Kitamura*
Division of Cellular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
International Radiation Information Center, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
* Corresponding author; email: kitamura{at}ims.u-tokyo.ac.jp.
Myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder characterized by tri-lineage dysplasia and susceptibility to acute myelogenous leukemia. Analysis of molecular basis of MDS has been hampered by the heterogeneity of the disease. Recently, mutations of a transcription factor AML1/RUNX1 have been identified in 15-40% of MDS-RAEB and MDS/AML. We performed mouse bone marrow transplantation (BMT) using bone marrow cells transduced with the AML1 mutants. Most mice developed MDS and MDS/AML-like symptoms within 4-13 months after BMT. Interestingly, among integration sites identified, Evi1 seemed to collaborate with an AML1 mutant harboring a point mutation in the Runt homology domain (D171N) to induce MDS/AML with an identical phenotype characterized by marked hepatosplenomegaly, myeloid dysplasia, leukocytosis, and biphenotypic surface markers. Collaboration between AML1-D171N and Evi1 was confirmed by a BMT model where coexpression of AML1-D171N and Evi1 induced acute leukemia of the same phenotype with much shorter latencies. On the other hand, a C-terminal truncated AML1 mutant (S291fsX300) induced pancytopenia with erythroid dysplasia in transplanted mice, followed by progression to MDS-RAEB or MDS/AML. Thus, we have developed a useful mouse model of MDS/AML that should help understand the molecular basis of MDS and the progression of MDS to overt leukemia.
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