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      Altered NFE2 activity predisposes to leukemic transformation and myelosarcoma with AML-specific aberrations

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          Key Points

          • Patients with AML acquire mutations in the transcription factor NFE2.

          • In mice, mutant NFE2 induces myeloproliferative neoplasms with subsequent transformation to AML and acquisition of AML-specific genetic alterations.

          Abstract

          In acute myeloid leukemia (AML), acquired genetic aberrations carry prognostic implications and guide therapeutic decisions. Clinical algorithms have been improved by the incorporation of novel aberrations. Here, we report the presence and functional characterization of mutations in the transcription factor NFE2 in patients with AML and in a patient with myelosarcoma. We previously described NFE2 mutations in patients with myeloproliferative neoplasms and demonstrated that expression of mutant NFE2 in mice causes a myeloproliferative phenotype. Now, we show that, during follow-up, 34% of these mice transform to leukemia presenting with or without concomitant myelosarcomas, or develop isolated myelosarcomas. These myelosarcomas and leukemias acquired AML-specific alterations, including the murine equivalent of trisomy 8, loss of the AML commonly deleted region on chromosome 5q, and mutations in the tumor suppressor Trp53. Our data show that mutations in NFE2 predispose to the acquisition of secondary changes promoting the development of myelosarcoma and/or AML.

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          Author and article information

          Journal
          Blood
          Blood
          bloodjournal
          blood
          Blood
          Blood
          American Society of Hematology (Washington, DC )
          0006-4971
          1528-0020
          18 April 2019
          12 February 2019
          18 April 2019
          : 133
          : 16
          : 1766-1777
          Affiliations
          [1 ]Section of Molecular Hematology, Department of Medicine I, Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany;
          [2 ]Department of Human Genetics, Hannover Medical School, Hannover, Germany;
          [3 ]Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands;
          [4 ]Institute for Surgical Pathology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany;
          [5 ]Hôpital Saint-Louis, Paris 7 University, Service d’Hématologie Adulte, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France;
          [6 ]APHP, Hôpital Saint-Louis, Laboratoire de Biologie Cellulaire, Paris, France;
          [7 ]Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany; and
          [8 ]Department of Hematology, Oncology and Tumor Immunology, Charité-University Medicine Berlin, Campus Virchow Klinikum, Berlin, Germany
          Author information
          http://orcid.org/0000-0002-1977-153X
          http://orcid.org/0000-0001-8797-0816
          http://orcid.org/0000-0002-8575-9213
          http://orcid.org/0000-0002-1118-017X
          http://orcid.org/0000-0001-8178-1571
          http://orcid.org/0000-0002-6514-3905
          http://orcid.org/0000-0002-5890-5510
          http://orcid.org/0000-0001-5256-1270
          http://orcid.org/0000-0003-2857-2396
          Article
          PMC6484461 PMC6484461 6484461 2019/875047
          10.1182/blood-2018-09-875047
          6484461
          30755419
          f6b0eb23-7739-469c-a668-4796828d8ba4
          © 2019 by The American Society of Hematology
          History
          : 13 September 2018
          : 05 February 2019
          Page count
          Pages: 12
          Categories
          33
          Myeloid Neoplasia
          Custom metadata
          free

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