AML1 mutations induced MDS and MDS/AML in a mouse BMT model Naoko Watanabe-Okochi

Naoko Watanabe-Okochi, Jiro Kitaura, Ryoichi Ono, Hironori Harada, Yuka Harada, Yukiko Komeno, Hideaki Nakajima, Tetsuya Nosaka, Toshiya Inaba, Toshio Kitamura

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Abstract

Myelodysplastic syndrome (MDS) is a hematopoietic stem-cell disorder characterized by trilineage dysplasia and susceptibility to acute myelogenous leukemia (AML). Analysis of molecular basis of MDS has been hampered by the heterogeneity of the disease. Recently, mutations of the transcription factor AML1/RUNX1 have been identified in 15% to 40% of MDS-refractory anemia with excess of blasts (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 to 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 (S291fs×300) 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 in the understanding of the molecular basis of MDS and the progression of MDS to overt leukemia.

Original languageEnglish
Pages (from-to)4297-4308
Number of pages12
JournalBlood
Volume111
Issue number8
DOIs
Publication statusPublished - 2008 Apr 15
Externally publishedYes

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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Watanabe-Okochi, N., Kitaura, J., Ono, R., Harada, H., Harada, Y., Komeno, Y., Nakajima, H., Nosaka, T., Inaba, T., & Kitamura, T. (2008). AML1 mutations induced MDS and MDS/AML in a mouse BMT model Naoko Watanabe-Okochi. Blood, 111(8), 4297-4308. https://doi.org/10.1182/blood-2007-01-068346