TY - JOUR
T1 - Altered NFE2 activity predisposes to leukemic transformation and myelosarcoma with AML-specific aberrations
AU - Jutzi, Jonas Samuel
AU - Basu, Titiksha
AU - Pellmann, Maximilian
AU - Kaiser, Sandra
AU - Steinemann, Doris
AU - Sanders, Mathijs A.
AU - Hinai, Adil S.A.
AU - Zeilemaker, Annelieke
AU - Kovacs, Sarolta Bojtine
AU - Koellerer, Christoph
AU - Ostendorp, Jenny
AU - Aumann, Konrad
AU - Wang, Wei
AU - Raffoux, Emmanuel
AU - Cassinat, Bruno
AU - Bullinger, Lars
AU - Schlegelberger, Brigitte
AU - Valk, Peter J.M.
AU - Pahl, Heike Luise
N1 - Publisher Copyright:
© 2019 by The American Society of Hematology
PY - 2019/4/18
Y1 - 2019/4/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85065016013&partnerID=8YFLogxK
U2 - 10.1182/blood-2018-09-875047
DO - 10.1182/blood-2018-09-875047
M3 - Article
C2 - 30755419
AN - SCOPUS:85065016013
SN - 0006-4971
VL - 133
SP - 1766
EP - 1777
JO - Blood
JF - Blood
IS - 16
ER -