Development of a novel therapeutic method against acute megakaryoblastic leukemia by NOTCH agonists

2017 Fiscal Year Final Research Report

• Project/Area Number: 15H04312
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Kumamoto University
• Principal Investigator: Osato Motomi 熊本大学, 国際先端医学研究機構, 特別招聘教授 (90314286)
• Co-Investigator(Kenkyū-buntansha): 横溝 智雅 熊本大学, 国際先端医学研究機構, 特定事業研究員 (80590314)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 分子標的治療 / 癌 / トランスレーショナルリサーチ

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.

Free Research Field

総合生物