RUNX1/AML1 mutant collaborates with BMI1 overexpression in the development of human and murine myelodysplastic syndromes

Yuka Harada, Daichi Inoue, Ye Ding, Jun Imagawa, Noriko Doki, Hirotaka Matsui, Takashi Yahata, Hiromichi Matsushita, Kiyoshi Ando, Goro Sashida, Atsushi Iwama, Toshio Kitamura, Hironori Harada

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

RUNX1/AML1 mutations have been identified in myelodysplastic syndromes (MDSs). In a mouse bone marrow transplantation model, a RUNX1 mutant, D171N, was shown to collaborate with Evi1 in the development of MDSs; however, this is rare in humans. Using enforced expression in human CD341 cells, we showed that the D171N mutant, the most frequent target of mutation in the RUNX1 gene, had an increased self-renewal capacity, blocked differentiation, dysplasia in all 3 lineages, and tendency for immaturity, but no proliferation ability. BMI1 overexpression was observed in CD341 cells from the majority of MDS patients with RUNX1 mutations, but not in D171N-transduced human CD341 cells. Cotransduction of D171N and BMI1 demonstrated that BMI1 overexpression conferred proliferation ability to D171N-transduced cells in both human CD341 cells and a mouse bone marrow transplantation model. Stepwise transduction of D171N followed by BMI1 in human CD341 cells resulted in long-term proliferation with a retained CD341 cell fraction, which is quite similar to the phenotype in patients with higher-risk MDSs. Our results indicate that BMI1 overexpression is one of the second hit partner genes of RUNX1 mutations that contribute to the development of MDSs.

Original languageEnglish
Pages (from-to)3434-3446
Number of pages13
JournalBlood
Volume121
Issue number17
DOIs
Publication statusPublished - 2013 Apr 25
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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