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

Jonas Samuel Jutzi, Titiksha Basu, Maximilian Pellmann, Sandra Kaiser, Doris Steinemann, Mathijs A. Sanders, Adil S.A. Hinai, Annelieke Zeilemaker, Sarolta Bojtine Kovacs, Christoph Koellerer, Jenny Ostendorp, Konrad Aumann, Wei Wang, Emmanuel Raffoux, Bruno Cassinat, Lars Bullinger, Brigitte Schlegelberger, Peter J.M. Valk and Heike Luise Pahl

Key points

  • AML patients acquire mutations in the transcription factor NFE2.

  • In mice, mutant NFE2 induced MPN with subsequent transformation to AML and acquisition of AML-specific genetic alterations.


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 AML patients 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.

  • Submitted September 13, 2018.
  • Accepted February 5, 2019.