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CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia.
Riether, Carsten; Schürch, Christian M; Bührer, Elias D; Hinterbrandner, Magdalena; Huguenin, Anne-Laure; Hoepner, Sabine; Zlobec, Inti; Pabst, Thomas; Radpour, Ramin; Ochsenbein, Adrian F.
Afiliación
  • Riether C; Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
  • Schürch CM; Department of Medical Oncology, Inselspital, University Hospital and University of Bern, 3010 Bern, Switzerland.
  • Bührer ED; Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
  • Hinterbrandner M; Institute of Pathology, University of Bern, 3008 Bern, Switzerland.
  • Huguenin AL; Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
  • Hoepner S; Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
  • Zlobec I; Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
  • Pabst T; Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
  • Radpour R; Institute of Pathology, University of Bern, 3008 Bern, Switzerland.
  • Ochsenbein AF; Department of Medical Oncology, Inselspital, University Hospital and University of Bern, 3010 Bern, Switzerland.
J Exp Med ; 214(2): 359-380, 2017 02.
Article en En | MEDLINE | ID: mdl-28031480
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Transducción de Señal / Crisis Blástica / Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral / Ligando CD27 Tipo de estudio: Prognostic_studies Límite: Aged / Animals / Humans / Middle aged Idioma: En Revista: J Exp Med Año: 2017 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Transducción de Señal / Crisis Blástica / Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral / Ligando CD27 Tipo de estudio: Prognostic_studies Límite: Aged / Animals / Humans / Middle aged Idioma: En Revista: J Exp Med Año: 2017 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos