2018 Fiscal Year Final Research Report
Understanding of stem cell aging as the onset basis of hematopoietic tumors in elderly patients
| Project Area | Establishing a new paradigm of the pathogenesis of diseases through the understanding of stem cell aging |
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| Project/Area Number |
26115009
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| Research Category |
Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | National Hospital Organization Nagoya Medical Center (2015-2018)
Kyoto University (2014) |
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Principal Investigator |
Sanada Masashi 独立行政法人国立病院機構(名古屋医療センター臨床研究センター), その他部局等, 高度診断研究部長 (20529044)
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| Co-Investigator(Kenkyū-buntansha) |
横手 幸太郎 千葉大学, 大学院医学研究院, 教授 (20312944)
宮本 敏浩 九州大学, 医学研究院, 准教授 (70343324)
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| Research Collaborator |
Kikushige Yoshikane
Kataoka Keisuke
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| Project Period (FY) |
2014-07-10 – 2019-03-31
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| Keywords | 老化 / クローン造血 / 白血病幹細胞 / 早老症 / 骨髄異形成症候群 / 慢性リンパ性白血病 / マウスモデル |
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| Outline of Final Research Achievements |
It has been clarified that age-related clonal hematopoiesis (ARCH) is closely involved in the development process of MDS and AA. Furthermore, we elucidated the molecular pathogenesis of RNA spliceosome mutations that are frequently observed in MDS and ARCH. ARCH was not found in Werner syndrome (WS) patients as well as in MDS that developed from WS, suggesting the existence of different aging and tumor development mechanisms. We found that gene mutations identical to CLL cells were acquired at the hematopoietic stem cell level in most of CLL cases, and identified IRAK-3 molecules ectopically expressed in CLL cells as a tumorigenic mechanism from CLL stem cells. It was shown that tumor cells secrete galectin-9, which is a ligand of TML-3, a stem cell-specific molecule of AML, into autocrine. Using the CRISPR / Cas9 system, mice with deletion alleles of Wrn and senescence related gene and double deletion mice were generated.
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| Free Research Field |
分子遺伝学、造血器腫瘍
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| Academic Significance and Societal Importance of the Research Achievements |
多くの腫瘍性疾患において加齢は最大のリスク因子であり、細胞老化が腫瘍化と密接に関わることをゲノム解析により明らかとした。RNAスプライシング分子変異の分子病態の解明は、強力な抗がん剤治療が困難な高齢者MDSにおける治療開発に寄与することが期待される。早老症研究は老化研究において重要であるが、早老症との差異につながる知見を得た意義は大きい。本研究で作成したマウスモデルやWerner症候群の疾患レジストリは、今後の同症候群並びに老化研究の重要な基盤になると考える。
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