2014 Fiscal Year Final Research Report
Elucidation of Molecular Mechanisms of Refractory Leukemia: Diagnostic Implications of FLT3-ITD Associated Biomarkers for Drug Resistance.
| Project/Area Number |
24590709
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Laboratory medicine
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| Research Institution | Tokai University |
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Principal Investigator |
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| Project Period (FY) |
2012-04-01 – 2015-03-31
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| Keywords | Refractory Leukemia / Drug Resistance / Biomarker / FLT3-ITD |
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| Outline of Final Research Achievements |
In order to elucidate the molecular pathogenesis and diagnostic marker of refractory leukemia, molecular mechanisms of cytosine arabinoside resistant leukemia cell K562 cells which possess prognostically poor biomarkers, an internal tandem duplication (ITD) of the receptor tyrosine kinase FLT3. Microarray analysis of the FLT3-ITD-transduced K562 leukemia cell line revealed 311 up-regulated genes. Among them we found transcriptional induction by FLT3-ITD of the runt-domain-containing transcriptional factor RUNX3. FLT3-ITD increased RUNX3 promoter activity in a reporter assay, which was hampered by the inhibitors. shRNA knockdown of RUNX3 in the cells resulted in an increased sensitivity to Ara-C. Exogenous overexpression of RUNX3 per se in K562 cells resulted in enhanced Ara-C resistance. These results suggest that RUNX3 could be a prerequisite for Ara-C resistance via FLT3-ITD signaling, and thus an important candidate of biomarker of the refractory AML.
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| Free Research Field |
病態検査学
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