TGF-Β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia

金沢大学がん研究所がん幹細胞研究センターChronic myeloid leukaemia (CML) is caused by a defined genetic abnormality that generates BCR-ABL, a constitutively active tyrosine kinase. It is widely believed that BCR-ABL activates Akt signalling that suppresses the forkhead O transcription factors (FOXO), supporting the proliferation or inhibiting the apoptosis of CML cells. Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemia-initiating cells (LICs) that drive the recurrence of CML. Here, using a syngeneic transplantation system and a CML-like myeloproliferative disease mouse model, we show that Foxo3a has an essential role in the maintenance of CML LICs. We find that cells with nuclear localization of Foxo3a and decreased Akt phosphorylation are enriched in the LIC population. Serial transplantation of LICs generated from Foxo3a+/+ and Foxo3a-/- mice shows that the ability of LICs to cause disease is significantly decreased by Foxo3a deficiency. Furthermore, we find that TGF-Β is a critical regulator of Akt activation in LICs and controls Foxo3a localization. A combination of TGF-Β inhibition, Foxo3a deficiency and imatinib treatment led to efficient depletion of CML in vivo. Furthermore, the treatment of human CML LICs with a TGF-Β inhibitor impaired their colony-forming ability in vitro. Our results demonstrate a critical role for the TGF-Β-FOXO pathway in the maintenance of LICs, and strengthen our understanding of the mechanisms that specifically maintain CML LICs in vivo. © 2010 Macmillan Publishers Limited. All rights reserved

Social entrepreneurship: problems and ways of their solution

For modern constantly developing societies, it is normal to create categories in the process of the activity of the participants of socio-economic processes themselves. Practice is theoretical, and theory is pragmatic, because it creates those concepts in which «practice» exists and develops. Such a category is "social entrepreneurship", which is "umbrella" for a number of socio-economic phenomena. The general term for social entrepreneurship includes those types of entrepreneurial activity that contradict the traditional notion of entrepreneurship as an activity of independent economic entities aimed at maximizing their profits. The development of social entrepreneurship is an indicator of the quality of the business climate in the region and requires a set of measures to ensure the mechanism and access of non-governmental organizations to the provision of services in the social sphere, the provision of state support to socially-oriented non-profit organizations, and the promotion of the development of PPP practices in the social sphere

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京都大学0048新制・課程博士博士(医学)甲第13338号医博第3150号新制||医||958(附属図書館)UT51-2007-M961京都大学大学院医学研究科分子医学系専攻(主査)教授 髙橋 良輔, 教授 瀬原 淳子, 教授 影山 龍一郎学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

mTORC1 is essential for leukemia propagation but not stem cell self-renewal

Although dysregulation of mTOR complex 1 (mTORC1) promotes leukemogenesis, how mTORC1 affects established leukemia is unclear. We investigated the role of mTORC1 in mouse hematopoiesis using a mouse model of conditional deletion of Raptor, an essential component of mTORC1. Raptor deficiency impaired granulocyte and B cell development but did not alter survival or proliferation of hematopoietic progenitor cells. In a mouse model of acute myeloid leukemia (AML), Raptor deficiency significantly suppressed leukemia progression by causing apoptosis of differentiated, but not undifferentiated, leukemia cells. mTORC1 did not control cell cycle or cell growth in undifferentiated AML cells in vivo. Transplantation of Raptor-deficient undifferentiated AML cells in a limiting dilution revealed that mTORC1 is essential for leukemia initiation. Strikingly, a subset of AML cells with undifferentiated phenotypes survived long-term in the absence of mTORC1 activity. We further demonstrated that the reactivation of mTORC1 in those cells restored their leukemia-initiating capacity. Thus, AML cells lacking mTORC1 activity can self-renew as AML stem cells. Our findings provide mechanistic insight into how residual tumor cells circumvent anticancer therapies and drive tumor recurrence