TY - JOUR
T1 - C/EBPb is a critical mediator of IFN-a–induced exhaustion of chronic myeloid leukemia stem cells
AU - Yokota, Asumi
AU - Hirai, Hideyo
AU - Sato, Ryuichi
AU - Adachi, Hiroko
AU - Sato, Fumiko
AU - Hayashi, Yoshihiro
AU - Sato, Atsushi
AU - Kamio, Naoka
AU - Miura, Yasuo
AU - Nakano, Masakazu
AU - Tenen, Daniel G.
AU - Kimura, Shinya
AU - Tashiro, Kei
AU - Maekawa, Taira
PY - 2019/2/12
Y1 - 2019/2/12
N2 - 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-a (IFN-a) 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-a upregulated CCAAT/enhancer binding protein b (C/EBPb) in BCR-ABL–expressing mouse cells by activating STAT1 and STAT5, which were recruited to a newly identified 39 distal enhancer of Cebpb that contains tandemly aligned IFN-g–activated site elements. Suppression or deletion of the IFN-g–activated site elements abrogated IFN-a–dependent upregulation of C/EBPb. IFN-a induced differentiation and exhaustion of CML stem cells, both in vitro and in vivo, in a C/EBPb-dependent manner. In addition, IFN-a upregulated C/EBPb and induced exhaustion of lineage2 CD341 cells from CML patients. Collectively, these results clearly indicate that C/EBPb is a critical mediator of IFN-a–induced differentiation and exhaustion of CML stem cells.
AB - 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-a (IFN-a) 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-a upregulated CCAAT/enhancer binding protein b (C/EBPb) in BCR-ABL–expressing mouse cells by activating STAT1 and STAT5, which were recruited to a newly identified 39 distal enhancer of Cebpb that contains tandemly aligned IFN-g–activated site elements. Suppression or deletion of the IFN-g–activated site elements abrogated IFN-a–dependent upregulation of C/EBPb. IFN-a induced differentiation and exhaustion of CML stem cells, both in vitro and in vivo, in a C/EBPb-dependent manner. In addition, IFN-a upregulated C/EBPb and induced exhaustion of lineage2 CD341 cells from CML patients. Collectively, these results clearly indicate that C/EBPb is a critical mediator of IFN-a–induced differentiation and exhaustion of CML stem cells.
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U2 - 10.1182/bloodadvances.2018020503
DO - 10.1182/bloodadvances.2018020503
M3 - Article
C2 - 30755436
AN - SCOPUS:85061508534
VL - 3
SP - 476
EP - 488
JO - Blood advances
JF - Blood advances
SN - 2473-9529
IS - 3
ER -