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J Exp Med. 2017 Feb;214(2):359-380. doi: 10.1084/jem.20152008. Epub 2016 Dec 28.

CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia.

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Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
Department of Medical Oncology, Inselspital, University Hospital and University of Bern, 3010 Bern, Switzerland.
Institute of Pathology, University of Bern, 3008 Bern, Switzerland.
Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland


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.

[Indexed for MEDLINE]
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