Elucidation of the roles of extracellular microsomes in donor cell-derived leukemia

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K19681
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Internal medicine of the bio-information integration and related fields
• Research Institution: Kanazawa University
• Principal Investigator: Mukaida Naofumi 金沢大学, がん進展制御研究所, 教授 (30182067)
• Co-Investigator(Kenkyū-buntansha): 馬場 智久 金沢大学, がん進展制御研究所, 准教授 (00452095)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Keywords: 骨髄異形成症候群 / 細胞外小胞 / ドナー細胞由来白血病 / STING / 骨髄移植 / BCR-ABL / 慢性骨髄性白血病

Outline of Final Research Achievements

Mice with BCR-ABL-positive chronic myelogenous leukemia (CML) developed donor cell-derived leukemia (DCL), myelodysplastic syndrome with donor cell-derived granulocytes with aberrant nuclear morphology and severe anemia, when normal donor cells were transplanted after irradiation. Recipient leukemia cell-derived extravesicles abundantly contain double-stranded DNA (dsDNA), which was horizontally transmitted into donor cells. In vitro studies demonstrated that dsDNA activated STING and subsequently interferon pathways in donor cells, thereby inhibiting replication capacity of donor hematopoietic stem/progenitor cells. Moreover, CML mice did not develop DCL when they received STING-deficient mouse-derived bone marrow cells after irradiation.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

本研究の結果から、CML細胞由来の細胞外小胞がSTING経路を介して、ドナー由来の骨髄幹細胞に対して抑制的に作用することによって、DCLが発症する可能性が強く示唆された。したがって、STING経路の抑制によって、治療法が確立されておらず、予後が不良なDCLの発症を予防できる可能性も示唆された。