FLT3-ITD upregulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation
| Project/Area Number |
20390272
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Kyushu University |
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Principal Investigator |
TOSHIHIRO Miyamoto Kyushu University, 大学病院・血液腫瘍内科, 講師 (70343324)
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| Co-Investigator(Kenkyū-buntansha) |
KOICHI Akashi 九州大学, 大学院・医学研究院, 教授 (80380385)
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| Project Period (FY) |
2008 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000)
Fiscal Year 2010: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2009: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2008: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000)
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| Keywords | 急性骨髄性白血病 / 白血病幹細胞 / MCL-1 / FLT-3 / アポトーシス / 白血病斡細胞 |
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| Research Abstract |
MCL-1 is an essential survival factor for hematopoiesis. We show that this FLT3-dependent stem cell maintenance system plays a critical role in survival of leukemic stem cells (LSCs) in acute myeloid leukemia (AML). The CD34^+CD38- LSC fraction expresses high levels of FLT3 as well as MCL-1, as compared even to normal HSCs. Treatment with FLT3 ligand induced further MCL-1 upregulation in LSCs in all AML cases tested. Interestingly, the group of samples expressing highest levels of MCL-1 constituted AML with FLT3-internal tandem duplications (ITD). In FLT3-ITD AML cell lines, cells expressed a high level of MCL-1, and an inhibition of MCL-1 induced their apoptotic cell death. A tyrosine kinase inhibitor suppressed MCL-1 expression, and induced apoptosis that was reversed by the enforced MCL-1 expression. Transduction of FLT3-ITD into HSCs strongly activated MCL-1 expression through its STAT5 docking domains. This effect was completely abrogated when STAT5 activation is blocked. Acquisition of FLT3-ITD ensures LSC survival by upregulating MCL-1 via constitutive STAT5 activation that is independent of wild-type FLT3 signaling.
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Report
(4 results)
Research Products
(41 results)
