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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\u2013receptor 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.<\/jats:p>","DOI":"10.1084\/jem.20152008","type":"journal-article","created":{"date-parts":[[2016,12,28]],"date-time":"2016-12-28T10:10:20Z","timestamp":1482919820000},"page":"359-380","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":184,"title":["CD70\/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia"],"prefix":"10.1084","volume":"214","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7512-513X","authenticated-orcid":true,"given":"Carsten","family":"Riether","sequence":"first","affiliation":[{"name":"Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland 1"},{"name":"Department of Medical Oncology, Inselspital, University Hospital and University of Bern, 3010 Bern, Switzerland 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1792-1768","authenticated-orcid":true,"given":"Christian M.","family":"Sch\u00fcrch","sequence":"additional","affiliation":[{"name":"Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland 1"},{"name":"Institute of Pathology, University of Bern, 3008 Bern, Switzerland 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5678-9395","authenticated-orcid":true,"given":"Elias D.","family":"B\u00fchrer","sequence":"additional","affiliation":[{"name":"Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Hinterbrandner","sequence":"additional","affiliation":[{"name":"Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Laure","family":"Huguenin","sequence":"additional","affiliation":[{"name":"Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Hoepner","sequence":"additional","affiliation":[{"name":"Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inti","family":"Zlobec","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University of Bern, 3008 Bern, Switzerland 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Pabst","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Inselspital, University Hospital and University of Bern, 3010 Bern, Switzerland 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5632-7833","authenticated-orcid":true,"given":"Ramin","family":"Radpour","sequence":"additional","affiliation":[{"name":"Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1773-5436","authenticated-orcid":true,"given":"Adrian F.","family":"Ochsenbein","sequence":"additional","affiliation":[{"name":"Tumor Immunology, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland 1"},{"name":"Department of Medical Oncology, Inselspital, University Hospital and University of Bern, 3010 Bern, Switzerland 3"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2016,12,28]]},"reference":[{"key":"2023072603463136700_bib1","first-page":"35","article-title":"Hematopoietic cell differentiation: Monoclonal antibodies and cluster designation defined hematopoietic cell antigens","volume-title":"Flow Cytometry in Clinical Diagnosis.","author":"Aoun","year":"2007","edition":"Fourth edition"},{"key":"2023072603463136700_bib2","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1182\/blood.V77.9.2031.2031","article-title":"Establishment of a human acute myeloid leukemia cell line (Kasumi-1) with 8;21 chromosome translocation","volume":"77","author":"Asou","year":"1991","journal-title":"Blood."},{"key":"2023072603463136700_bib3","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1158\/0008-5472.CAN-14-2750","article-title":"Fearful symmetry: subversion of asymmetric division in cancer development and progression","volume":"75","author":"Bajaj","year":"2015","journal-title":"Cancer Res."},{"key":"2023072603463136700_bib4","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1172\/JCI71264","article-title":"HSC commitment-associated epigenetic signature is prognostic in acute myeloid leukemia","volume":"124","author":"Bartholdy","year":"2014","journal-title":"J. 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