C/EBP? is a critical mediator of IFN-?-induced exhaustion of chronic myeloid leukemia stem cells.

ABSTRACT: 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-? (IFN-?) 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-? upregulated CCAAT/enhancer binding protein ? (C/EBP?) 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-?-activated site elements. Suppression or deletion of the IFN-?-activated site elements abrogated IFN-?-dependent upregulation of C/EBP?. IFN-? induced differentiation and exhaustion of CML stem cells, both in vitro and in vivo, in a C/EBP?-dependent manner. In addition, IFN-? upregulated C/EBP? and induced exhaustion of lineage- CD34+ cells from CML patients. Collectively, these results clearly indicate that C/EBP? is a critical mediator of IFN-?-induced differentiation and exhaustion of CML stem cells.

SUBMITTER: Yokota A 

PROVIDER: S-EPMC6373744 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature