2023 Fiscal Year Final Research Report
PML-RARA of the short but long isoform initiate from TIM-3+ leukemic stem cells with hierarchical leukemic organization
| Project/Area Number |
22K19544
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
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| Research Institution | Kanazawa University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
菊繁 吉謙 九州大学, 大学病院, 講師 (40619706)
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| Project Period (FY) |
2022-06-30 – 2024-03-31
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| Keywords | APL / 白血病幹細胞 / PML::RARA |
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| Outline of Final Research Achievements |
LSC of AML can be enriched in CD34+CD38- fraction and reconstitute human AML in vivo. However, in APL, which constitutes 10% of all AML and is driven by PML::RARA fusion genes, the presence of LSC has long been unidentified because of difficulty in reconstitution of APL. We show that LSC of short-type isoform APL, defined by different breakpoints of PML, concentrate in CD34+CD38- fraction and express TIM-3. Short-type APL exhibited distinct gene expression signatures, including LSC-related genes, compared to the other types. CD34+CD38-TIM-3+ short-type APL efficiently reconstituted APL in xenograft with high penetration, whereas CD34- differentiated APL cells did not. CD34+CD38-TIM-3+ short-type APL reconstituted APL after serial transplantation. Identification of LSC in a subset of APL and establishment of an efficient patient-derived xenograft model may contribute to further understanding APL leukemogenesis and devise individual treatments for eradication of APL LSC.
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| Free Research Field |
血液内科学
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| Academic Significance and Societal Importance of the Research Achievements |
APLは異種移植系で安定して白血病を再構築可能な白血病幹細胞分画は報告されておらず、本研究が初めてAPL幹細胞の存在を明らかにした。また同一のPML::RARA融合遺伝子であってもゲノム切断部位で違うshort-typeとlong-typeで、初めて異なる白血化機構を解明した独自性の高い研究である。従来、APLはPML::RARA融合遺伝子獲得のみの単純な発症様式と考えられていたが、多様性に富む白血病である可能性を示した。今後は2つのタイプの白血化機構の相違を明らかにし、各病型に特化した標的治療が開発できれば、新規APL標的治療としてブレイクスルーとなる。
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