RUNX3 over-expression promotes the development of myelodysplastic syndrome
| Project/Area Number |
16K19579
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Hematology
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| Research Institution | Kumamoto University |
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Principal Investigator |
Yokomizo Takako 熊本大学, 国際先端医学研究機構, 特別研究員(RPD) (40636867)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | Runx3 / MDS / エンハンサー / Myc / Runx1 / 白血病 / RUNX3 / MYC / CRISPR / 癌 |
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| Outline of Final Research Achievements |
RUNX3 functions as either tumor suppressor or oncogene, however, it remains unknown how RUNX3 promotes the formation of myeloid malignancies including MDS. We found that RUNX3 expression was significantly increased in patients with progressive MDS. We hypothesized that RUNX3 promotes the development of MDS via super enhancer formation of RUNX3.
To determine how RUNX3 promotes the formation of MDS, we generated a hematopoietic-specific Tet2 null and RUNX3 overexpressing (Tet2KO-RUNX3) mouse model. Tet2KO-RUNX3 MDS cells suppressed differentiation genes, but activated myc-related biological pathways such as ribosome, mitochondria, and cell cycle progression. Since FLT3-ITD+ MV4-11 AML has been shown to activate enhancers of RUNX3 (eRX3), Cas9-sgRNA-directed eRX3 significantly reduced expression of RUNX3 and lead to impairing the proliferative capacity. Thus, RUNX3 and C-MYC cooperatively promote the development of MDS in TET2 deficient cells via formation of oncogenic enhancers.
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| Academic Significance and Societal Importance of the Research Achievements |
骨髄異形成症候群(MDS)は造血幹細胞より発生するクローン性造血器腫瘍であり、一部が急性骨髄性白血病(AML)に移行する高齢者に好発するがんである。近年の網羅的な遺伝子変異解析によって、TET2などのエピゲノム制御遺伝子変異が同定され、エピゲノム制御の破綻がMDS発症に深く関与することが認識された。近年、健常高齢者でTET2変異を伴ったクローナル造血が高頻度に存在することが明らかとなったが、MDS発症に至るには付加的なゲノムまたエピゲノム変異が不可欠であり、責任遺伝子を含めたMDS発症とAMLへの病態進展のメカニズムは未だ明白でない。本研究成果はそのメカニズム解明の一端となるものと考える。
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Report
(4 results)
Research Products
(3 results)
