RUNX1/AML1 mutant collaborates with BMI1 overexpression in the development of human and murine myelodysplastic syndromes
| Autor: | Daichi Inoue, Hironori Harada, Kiyoshi Ando, Goro Sashida, Hirotaka Matsui, Jun Imagawa, Yuka Harada, Toshio Kitamura, Ye Ding, Noriko Doki, Atsushi Iwama, Hiromichi Matsushita, Takashi Yahata |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Bone marrow transplantation Blotting Western Immunology Mutant CD34 Antigens CD34 Biology Real-Time Polymerase Chain Reaction medicine.disease_cause Biochemistry Mice chemistry.chemical_compound hemic and lymphatic diseases medicine Animals Humans Runx1 aml1 RNA Messenger Aged Bone Marrow Transplantation Cell Proliferation Polycomb Repressive Complex 1 Mutation Reverse Transcriptase Polymerase Chain Reaction Myelodysplastic syndromes Cell Differentiation Cell Biology Hematology Flow Cytometry medicine.disease Mice Inbred C57BL Cell Transformation Neoplastic Phenotype RUNX1 chemistry BMI1 Myelodysplastic Syndromes Core Binding Factor Alpha 2 Subunit embryonic structures Cancer research |
| Zdroj: | Blood. 121:3434-3446 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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 CD34(+) 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 CD34(+) cells from the majority of MDS patients with RUNX1 mutations, but not in D171N-transduced human CD34(+) cells. Cotransduction of D171N and BMI1 demonstrated that BMI1 overexpression conferred proliferation ability to D171N-transduced cells in both human CD34(+) cells and a mouse bone marrow transplantation model. Stepwise transduction of D171N followed by BMI1 in human CD34(+) cells resulted in long-term proliferation with a retained CD34(+) 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. |
| Databáze: | OpenAIRE |
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