1. CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia
- Author
-
Anne Laure Huguenin, Sabine Hoepner, Magdalena Hinterbrandner, Elias D. Bührer, Thomas Pabst, Christian M. Schürch, Ramin Radpour, Adrian F. Ochsenbein, Carsten Riether, and Inti Zlobec
- Subjects
0301 basic medicine ,Myeloid ,Immunology ,610 Medicine & health ,chemical and pharmacologic phenomena ,Protein Serine-Threonine Kinases ,Biology ,Article ,Germinal Center Kinases ,Mice ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Precursor cell ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Immunology and Allergy ,Progenitor cell ,Wnt Signaling Pathway ,neoplasms ,Research Articles ,Aged ,Wnt signaling pathway ,Antibodies, Monoclonal ,Myeloid leukemia ,hemic and immune systems ,Middle Aged ,TNF Receptor-Associated Factor 2 ,medicine.disease ,Tumor Necrosis Factor Receptor Superfamily, Member 7 ,3. Good health ,Leukemia, Myeloid, Acute ,Haematopoiesis ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,570 Life sciences ,biology ,Stem cell ,Blast Crisis ,CD27 Ligand ,Signal Transduction - Abstract
Riether et al. show that CD70/CD27 signaling activates stem cell gene expression programs in acute myeloid leukemia (AML). Blocking the CD70/CD27 interaction inhibits self-renewal and induces differentiation of AML blasts and stem/progenitor cells., 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.
- Published
- 2016