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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.

Author information

1
Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
2
Department of Medical Oncology, Inselspital, University Hospital and University of Bern, 3010 Bern, Switzerland.
3
Institute of Pathology, University of Bern, 3008 Bern, Switzerland.
4
Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland adrian.ochsenbein@insel.ch.

Abstract

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.

PMID:
28031480
PMCID:
PMC5294846
DOI:
10.1084/jem.20152008
[Indexed for MEDLINE]
Free PMC Article

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