title: CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia.
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.
authors.affiliation: 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.
authors.forename: Carsten
authors.identifier: 0000-0001-7512-513X
authors.initials: C
authors.lastname: Riether
authors.affiliation: Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.|Institute of Pathology, University of Bern, 3008 Bern, Switzerland.
authors.forename: Christian M
authors.identifier: 0000-0002-1792-1768
authors.initials: CM
authors.lastname: Schürch
authors.affiliation: Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
authors.forename: Elias D
authors.identifier: 0000-0001-5678-9395
authors.initials: ED
authors.lastname: Bührer
authors.affiliation: Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Hinterbrandner
authors.affiliation: Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Huguenin
authors.affiliation: Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hoepner
authors.affiliation: Institute of Pathology, University of Bern, 3008 Bern, Switzerland.
authors.forename: Inti
authors.initials: I
authors.lastname: Zlobec
authors.affiliation: Department of Medical Oncology, Inselspital, University Hospital and University of Bern, 3010 Bern, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pabst
authors.affiliation: Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
authors.forename: Ramin
authors.identifier: 0000-0002-5632-7833
authors.initials: R
authors.lastname: Radpour
authors.affiliation: Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland adrian.ochsenbein@insel.ch.|Department of Medical Oncology, Inselspital, University Hospital and University of Bern, 3010 Bern, Switzerland.
authors.forename: Adrian F
authors.identifier: 0000-0003-1773-5436
authors.initials: AF
authors.lastname: Ochsenbein
mesh_terms: D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001752:Blast Crisis / Q000209:etiology*; D053282:CD27 Ligand / Q000037:antagonists & inhibitors / Q000502:physiology*; D000081410:Germinal Center Kinases; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D047992:TNF Receptor-Associated Factor 2 / Q000502:physiology; D014407:Tumor Cells, Cultured; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D053282:CD27 Ligand; C505771:CD70 protein, human; D000081410:Germinal Center Kinases; C101338:PSMD2 protein, human; D047992:TNF Receptor-Associated Factor 2; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D017346:Protein Serine-Threonine Kinases