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C/EBPβ is a Critical Mediator of IFN-α-induced Exhaustion of Chronic Myeloid Leukemia Stem Cells

Overview
Journal Blood Adv
Specialty Hematology
Date 2019 Feb 14
PMID 30755436
Citations 13
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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-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 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.

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