C/EBPβ is a critical mediator of IFN-α–induced exhaustion of chronic myeloid leukemia stem cells

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-alpha (IFN-alpha) 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-alpha upregulated CCAAT/enhancer binding protein beta (C/EBP beta) in BCR-ABL-expressing mouse cells by activating STAT1 and STAT5, which were recruited to a newly identified 39 distal enhancer of Cebp beta that contains tandemly aligned IFN-gamma-activated site elements. Suppression or deletion of the IFN-gamma-activated site elements abrogated IFN-alpha-dependent upregulation of C/EBP beta. IFN-alpha induced differentiation and exhaustion of CML stem cells, both in vitro and in vivo, in a C/EBP beta-dependent manner. In addition, IFN-alpha upregulated C/EBP beta and induced exhaustion of lineage2 CD341 cells from CML patients. Collectively, these results clearly indicate that C/EBP beta is a critical mediator of IFN-alpha-induced differentiation and exhaustion of CML stem cells.