CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia.
- Riether C Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
- Schürch CM Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
- Bührer ED Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
- Hinterbrandner M Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
- Huguenin AL Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
- Hoepner S Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
- Zlobec I Institute of Pathology, University of Bern, 3008 Bern, Switzerland.
- Pabst T Department of Medical Oncology, Inselspital, University Hospital and University of Bern, 3010 Bern, Switzerland.
- Radpour R Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
- Ochsenbein AF Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland adrian.ochsenbein@insel.ch.
- 2016-12-30
Published in:
- The Journal of experimental medicine. - 2017
Aged
Animals
Antibodies, Monoclonal
Blast Crisis
CD27 Ligand
Germinal Center Kinases
Humans
Leukemia, Myeloid, Acute
Mice
Middle Aged
Protein-Serine-Threonine Kinases
Signal Transduction
TNF Receptor-Associated Factor 2
Tumor Cells, Cultured
Tumor Necrosis Factor Receptor Superfamily, Member 7
Wnt Signaling Pathway
English
Aberrant proliferation, symmetric self-renewal, increased survival, and defective differentiation of malignant blasts are key oncogenic drivers in acute myeloid leukemia (AML). Stem cell gene signatures predict poor prognosis in AML patients; however, with few exceptions, these deregulated molecular pathways cannot be targeted therapeutically. In this study, we demonstrate that the TNF superfamily ligand-receptor pair CD70/CD27 is expressed on AML blasts and AML stem/progenitor cells. CD70/CD27 signaling in AML cells activates stem cell gene expression programs, including the Wnt pathway, and promotes symmetric cell divisions and proliferation. Soluble CD27, reflecting the extent of CD70/CD27 interactions in vivo, was significantly elevated in the sera of newly diagnosed AML patients and is a strong independent negative prognostic biomarker for overall survival. Blocking the CD70/CD27 interaction by mAb induced asymmetric cell divisions and differentiation in AML blasts and AML stem/progenitor cells, inhibited cell growth and colony formation, and significantly prolonged survival in murine AML xenografts. Importantly, hematopoietic stem/progenitor cells from healthy BM donors express neither CD70 nor CD27 and were unaffected by blocking mAb treatment. Therefore, targeting CD70/CD27 signaling represents a promising therapeutic strategy for AML.
- Language
-
- English
- Open access status
- hybrid
- Identifiers
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- DOI 10.1084/jem.20152008
- PMID 28031480
- Persistent URL
- https://sonar.rero.ch/global/documents/89852
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