2022 Fiscal Year Final Research Report
Development of novel antibodies against leukemia and elucidation of their blocking mechanisms
| Project/Area Number |
19K07668
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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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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | Kumamoto University |
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Principal Investigator |
Osato Motomi 熊本大学, 国際先端医学研究機構, 特定研究員 (90314286)
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| Co-Investigator(Kenkyū-buntansha) |
指田 吾郎 熊本大学, 国際先端医学研究機構, 特別招聘教授 (70349447)
岩崎 正幸 東京女子医科大学, 医学部, 講師 (70790913)
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Keywords | 白血病 / トランスレーショナルリサーチ / 分子標的治療 / ITGA9 / 抗体医薬 / がん幹細胞 |
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| Outline of Final Research Achievements |
Leukemia stem cells (LSCs), being largely dormant at steady state, are widely believed to reside in the bone marrow niches; however, the capacity of the BM niches for LSCs is limited, and most LSCs are being maintained outside the BM, namely the extramedullarly spaces. The molecular basis for this paradox remains elusive. Here, we show that integrin a9 overexpression (ITGA9 OE) plays a pivotal role in the extramedullary maintenance of LSCs by molecularly mimicking the niche-interacting status, through the binding with its soluble-form ligand, osteopontin (Opn). The binding of ITGA9 with soluble Opn, a known negative regulator against HSC activation, induced LSC dormancy, while the disruption of ITGA9-soluble Opn interaction caused rapid cell propagation. ITGA9 OE leads to both active leukemia cell proliferation and increase of dormant LSCs in a well-balanced manner, thereby maintaining LSCs extramedullarly. The ITGA9-Opn axis would serve as a novel therapeutic target in AML.
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| Free Research Field |
腫瘍生物学
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| Academic Significance and Societal Importance of the Research Achievements |
白血病に対する治療成績は依然として満足できるものではなく、大量の抗癌剤使用による副作用も大きな問題である。一方で、白血病発症分子機序に基づく分子標的治療[慢性骨髄性白血病に対するイマチニブ、前骨髄球性白血病に対するレチノイン酸(ATRA)など]は、ほぼ100%に迫るかのような劇的な奏功率と、化学療法のそれと比べるとほとんど問題にならない程度の副作用で治療現場を大きく変えた。今回、本研究で同定されたインテグリンアルファ９（ITGA９)高発現は白血病幹細胞の維持に極めて大事であり、抗ITGA９抗体によるその維持機構の遮断は残存白血病細胞の駆逐排除に有用な新規分子標的治療法として期待される。
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