Blood advances · 2019
C/EBPβ is a critical mediator of IFN-α-induced exhaustion of chronic myeloid leukemia stem cells.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Yokota Asumi, Hirai Hideyo, Sato Ryuichi, Adachi Hiroko, Sato Fumiko, Hayashi Yoshihiro, Sato Atsushi, Kamio Naoka, Miura Yasuo, Nakano Masakazu, Tenen Daniel G, Kimura Shinya, Tashiro Kei, Maekawa Taira
Аннотация
Even in the era of ABL tyrosine kinase inhibitors, eradication of chronic myeloid leukemia (CML) stem cells is necessary for complete cure of the disease. Interferon-α (IFN-α) has long been used for the treatment of chronic-phase CML, but its mechanisms of action against CML stem cells remain unclear. We found that IFN-α upregulated CCAAT/enhancer binding protein β (C/EBPβ) in BCR-ABL-expressing mouse cells by activating STAT1 and STAT5, which were recruited to a newly identified 3' distal enhancer of Cebpb that contains tandemly aligned IFN-γ-activated site elements. Suppression or deletion of the IFN-γ-activated site elements abrogated IFN-α-dependent upregulation of C/EBPβ. IFN-α induced differentiation and exhaustion of CML stem cells, both in vitro and in vivo, in a C/EBPβ-dependent manner. In addition, IFN-α upregulated C/EBPβ and induced exhaustion of lineage- CD34+ cells from CML patients. Collectively, these results clearly indicate that C/EBPβ is a critical mediator of IFN-α-induced differentiation and exhaustion of CML stem cells.