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

• DOI: 10.1084/jem.20152008
• Publication Date: 2016-12-28T15:10:20Z
• Authors: Carsten Riether; Christian M. Schürch; Elias D. Bührer; Magdalena Hinterb...; Anne-Laure Huguenin; Sabine Hoepner; Inti Zlobec; Thomas Pabst; Ramin Radpour; Adrian F. Ochsenbein
• Keywords: 0301 basic medicine; Antibodies, Monoclonal; 610 Medicine & health; Middle Aged; Protein Serine-Threonine Kinases; TNF Receptor-Associated Factor 2; Germinal Center Kinases; Tumor Necrosis Factor Receptor Superfamily, Member 7; 3. Good health; Leukemia, Myeloid, Acute; Mice; 03 medical and health sciences; Tumor Cells, Cultured; 570 Life sciences; biology; Animals; Humans; Blast Crisis; Wnt Signaling Pathway; Research Articles; Aged; CD27 Ligand; Signal Transduction

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 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 stem/progenitor cells. signaling cells activates stem expression programs, including Wnt pathway, promotes divisions proliferation. Soluble CD27, reflecting extent interactions vivo, was significantly elevated sera newly diagnosed patients a strong independent negative prognostic biomarker for overall survival. Blocking interaction by mAb induced asymmetric cells, inhibited growth colony formation, prolonged survival murine xenografts. Importantly, hematopoietic from healthy BM donors express neither CD70 nor CD27 were unaffected blocking treatment. Therefore, targeting represents promising therapeutic strategy AML.