Riether, Carsten; Schürch, Christian M.; Bührer, Elias D.; Hinterbrandner, Magdalena; Huguenin, Anne-Laure; Höpner, Sabine; Zlobec, Inti; Pabst, Thomas; Radpour, Ramin; Ochsenbein, Adrian F. (2017). CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia. The Journal of experimental medicine, 214(2), pp. 359-380. Rockefeller Univ. Press 10.1084/jem.20152008
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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.
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