期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 7, 期 298, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aab1740
关键词
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资金
- Swiss National Science Foundation [31003A_149768, 310030B_133132]
- Swiss Cancer League [KFS-2879-02-2012, KLS-02342-02-2009]
- Cancer League of the Canton of Bern
- Werner und Hedy Berger-Janser-Stiftung
- Bernese Foundation for Clinical Cancer Research
- Marlies Schwegler-Stiftung
- Sassella Foundation [12/01]
- Fondation Bios pour la Recherche
- Gertrud-Hagmann-Stiftung fur Malignom-Forschung
- SwissLife Jubilaumsstiftung
- Dr. Hans Altschuler-Stiftung
- Fondazione Dr. Carlo Gianella
- Mobiliar Jubilaumsstiftung
- Monika Kutzner Stiftung
- Stiftung Krebshilfe
- Wolfermann-Nageli-Stiftung
- Swiss National Science Foundation (SNF) [310030B_133132, 31003A_149768] Funding Source: Swiss National Science Foundation (SNF)
- European Hematology Association [TRTH117] Funding Source: researchfish
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 results in molecular remission of CML; however, LSCs persist long term despite BCR-ABL1 inhibition, ultimately causing disease relapse. We demonstrate that TKIs induce the expression of the tumor necrosis factor (TNF) family ligand CD70 in LSCs by down-regulating microRNA-29, resulting in reduced CD70 promoter DNA methylation and up-regulation of the transcription factor specificity protein 1. The resulting increase in CD70 triggered CD27 signaling and compensatory Wnt pathway activation. Combining TKIs with CD70 blockade effectively eliminated human CD34(+) CML stem/progenitor cells in xenografts and LSCs in a murine CML model. Therefore, targeting TKI-induced expression of CD70 and compensatory Wnt signaling resulting from the CD70/CD27 interaction is a promising approach to overcoming treatment resistance in CML LSCs.
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