2004 Fiscal Year Final Research Report Summary
Transcription factor regulation of malignant cell transformation and its repression
| Project/Area Number |
15027201
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | University of Tsukuba |
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Principal Investigator |
YAMAMOTO Masayuki University of Tsukuba Institute of Basic Medical sciences, Professor, 基礎医学系, 教授 (50166823)
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| Project Period (FY) |
2003 – 2004
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| Keywords | GATA-1 knockdown mouse / Apoptosis / Erythroid differentiation / Myelodysplastic syndrome / Leukemia / Down syndrome |
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| Research Abstract |
In this study we have studied transcription factor regulation of malignant cell transformation and its repression exploiting hematopoietic transcription factors and leukemia as a model system. GATA-1 is essential for the development of erythroid and megakaryocytic lineages and mutations leading to the production of N-terminus truncated form GATA-1 are frequently found in the Down syndrome-related acute megakaryoblastic leukemia (AMKL-DS) patients. We found that GATA-1 gene knockdown female (GATA-1.05/X) mice frequently develop a hematopoietic disorder that resembles myelodysplastic syndrome characterized by the accumulation of progenitors. We have demonstrated that GATA-1.05/X mice suffer from two distinct types of acute leukemias. Since GATA-1 is an X chromosomal gene, two types of hematopoietic cells reside within heterozygous GATA-1 knockdown mice, bearing either an active wild-type GATA-1 allele or an active mutant GATA-1.05 allele. In the latter hematopoietic progenitors, low-level GATA-1 expression is sufficient to support survival, but not differentiation, leading to the accumulation of progenitors that are easily targeted by oncogenic stimuli. Since such leukemia cases have not been observed in GATA-1-null/X mutant mice and since transgenic expression of wild-type GATA-1 rescue GATA-1.05/X mice from the leukemia, we conclude that the residual GATA-1 activity in the knockdown mice contributes to the development of the malignancy. In addition, wild-type GATA-1 promoted AMKL-DS leukemic cells to mature erythroid cells, but truncated form GATA-1 could not, suggesting that defect of GATA-1 is one of the leukemogenic factors.
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