IFN-α in CML: Mediator of CML Stem Cell Exhaustion Identified
Posted: Monday, March 18, 2019
Although interferon-α (IFN-α) has long been used IN the treatment of chronic-phase chronic myeloid leukemia (CML), its mechanism of action has remained unclear. In a study published in Blood Advances, researchers have discovered that CCAAT/enhancer binding protein β (C/EBPβ), a leucine-zipper transcription factor that plays important roles in granulopoiesis, appears to be a critical mediator of interferon-α–induced differentiation and exhaustion of CML stem cells.
Asumi Yokota, PhD, of Kyoto University Hospital, Japan, and colleagues found that IFN- α upregulated C/EBPβ in CML mouse cells by activating transcription factors STAT1 and STAT5. They also identified a novel 3' distal enhancer as a critical element for upregulation of Cebpb by the BCR-ABL–STAT5 axis. IFN- α recruits both STAT1 and STAT5 to this distal enhancer and induces differentiation of CML stem cells through further upregulation of Cebpb, promoting exhaustion of patient-derived CML stem and progenitor cells.
Dr. Yokota and colleagues assert that because the molecular mechanisms that mediate the effects of IFN- α differ from those involved in the response to tyrosine kinase inhibitor (TKI) therapy, a combination of these therapeutic approaches may be more effective than either alone to completely eliminate stray stem cells in bone marrow. “It remains to be determined whether CML can be cured using TKIs alone,” stated the researchers. “Eradication of CML stem cells would greatly benefit patients with chronic-phase CML.”
Disclosure: The study authors’ disclosure information may be found at bloodadvances.org.