2013 Fiscal Year Final Research Report
Overcoming therapy-resistant leukemia using EZH2 inhibitor
| Project/Area Number |
24890045
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Single-year Grants |
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| Research Field |
Hematology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
UEDA Koki 東京大学, 医学部附属病院, 助教 (80632190)
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| Project Period (FY) |
2012-08-31 – 2014-03-31
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| Keywords | EZH2 / MLL |
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| Research Abstract |
EZH2 inhibitor DZNep and shRNA for EZH2 strongly suppressed the proliferation of MLL-related leukemia cell lines and immortalized cells harboring MLL fusion genes with high specificity. In vivo administration of DZNep and transduction of shRNA targeting EZH2 decreased the leukemic granulocyte macrophage progenitors (LGMPs) and prolonged survival of MLL/AF9 and MLL/ENL-induced leukemic mice. Limiting dilution transplantation assay revealed that frequency of leukemia stem cells (LSCs) was reduced by DZNep administration. Expression analysis suggested that p16 up-regulation was responsible for LSC reduction. In fact, knockdown of p16 completely canceled the survival advantage of mice which received DZNep. Chromatin immunoprecipitation assays suggested that both H3K4 and H3K27 methylation marks were highly enriched around the TSS of p16, together with EZH2 and Bmi1. Therefore removal of EZH2 is supposed to convert the promoter of p16 to an active state.
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