| Budget Amount *help |
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2016: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2015: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
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| Outline of Final Research Achievements |
The genetic lesions that drive acute megakaryoblastic leukemia (AMKL) have not been fully elucidated. To search for AMKL genes, an AMKL mouse model was developed employing retroviral insertional mutagenesis (RIM) on the mouse carrying alterations in two known AMKL genes, Gata-1 and Runx1. RIM screening identified genetic abrogations in Notch and JAK-STAT pathways. Extending these findings in mouse to human, we performed targeted deep sequencing in 34 AMKL patient samples and 8 AMKL cell lines, and detected genetic mutations in Notch and JAK-STAT pathways. NOTCH activator, but not inhibitor, and JAK inhibitor significantly suppressed AMKL cell proliferation by inducing apoptosis individually as a single agent and synergistically as a combination therapy. Notably, this Notch activation is induced in a ligand-independent manner, revealing a novel mechanism that holds a potential of therapeutic application for AMKL.
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