title: MPN patients harbor recurrent truncating mutations in transcription factor NF-E2.
abstract: The molecular etiology of myeloproliferative neoplasms (MPNs) remains incompletely understood, despite recent advances incurred through the discovery of several different mutations in MPN patients. We have recently described overexpression of the transcription factor NF-E2 in MPN patients and shown that elevated NF-E2 levels in vivo cause an MPN phenotype and predispose to leukemic transformation in transgenic mice. We report the presence of acquired insertion and deletion mutations in the NF-E2 gene in MPN patients. These result in truncated NF-E2 proteins that enhance wild-type (WT) NF-E2 function and cause erythrocytosis and thrombocytosis in a murine model. NF-E2 mutant cells acquire a proliferative advantage, witnessed by clonal dominance over WT NF-E2 cells in MPN patients. Our data underscore the role of increased NF-E2 activity in the pathophysiology of MPNs.
authors.affiliation: Department of Hematology/Oncology, University Hospital Freiburg, 79106 Freiburg, Germany
authors.forename: Jonas S
authors.initials: JS
authors.lastname: Jutzi
authors.forename: Ruzhica
authors.initials: R
authors.lastname: Bogeska
authors.forename: Gorica
authors.initials: G
authors.lastname: Nikoloski
authors.forename: Corina A
authors.initials: CA
authors.lastname: Schmid
authors.forename: Thalia S
authors.initials: TS
authors.lastname: Seeger
authors.forename: Frank
authors.initials: F
authors.lastname: Stegelmann
authors.forename: Sven
authors.initials: S
authors.lastname: Schwemmers
authors.forename: Albert
authors.initials: A
authors.lastname: Gründer
authors.forename: Jan C
authors.initials: JC
authors.lastname: Peeken
authors.forename: Monika
authors.initials: M
authors.lastname: Gothwal
authors.forename: Julius
authors.initials: J
authors.lastname: Wehrle
authors.forename: Konrad
authors.initials: K
authors.lastname: Aumann
authors.forename: Kamar
authors.initials: K
authors.lastname: Hamdi
authors.forename: Christine
authors.initials: C
authors.lastname: Dierks
authors.forename: Wei
authors.initials: W
authors.lastname: Kamar  Wang
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Joop H
authors.initials: JH
authors.lastname: Jansen
authors.forename: Heike L
authors.initials: HL
authors.lastname: Pahl
mesh_terms: D000818:Animals; D019046:Bone Marrow Neoplasms / Q000235:genetics* / Q000473:pathology; D016026:Bone Marrow Transplantation; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation; D002999:Clone Cells; D004247:DNA / Q000378:metabolism; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D055550:Protein Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D050505:Mutant Proteins; D050984:NF-E2 Transcription Factor, p45 Subunit; C494692:NFE2 protein, human; D012333:RNA, Messenger; D004247:DNA; D053614:Janus Kinase 2