In chronic myelogenous leukemia (CML), oncogenic BCR-ABL1 activates the Wnt pathway, which is fundamental for leukemia stem cell (LSC) maintenance. Tyrosine kinase inhibitor (TKI) treatment reduces Wnt-signaling in LSCs and often leads to molecular remission of CML; however, LSCs persist long-term despite BCR-ABL1 inhibition, ultimately leading to disease relapse. Here, we demonstrate that TKIs induce the expression of the tumor necrosis factor (TNF) family ligand CD70in LSCs by down-regulating microRNA-29, resulting in reduced CD70 promoter DNA methylation and up-regulation of the transcription factor specificity protein 1. CD70 triggered CD27-signaling and compensatory Wnt pathway activation. Consequently, combining TKIs with CD70 blockade effectively eliminated human CD34 + CML stem/progenitor cells in xenografts and LSCs in a murine CML model. Therefore, TKI-induced expression of CD70 and compensatory Wnt-signaling via the CD70/CD27-interaction is a promising targetable resistance mechanism of CML LSCs.3

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