title: CEBPA double-mutated acute myeloid leukaemia harbours concomitant molecular mutations in 76·8% of cases with TET2 and GATA2 alterations impacting prognosis.
abstract: Acute myeloid leukaemia (AML) with CEBPA mutations is listed as a provisional entity in the current World Health Organization classification. A difference in clinical outcome between single- (sm) and double-mutated (dm) cases has been reported, whereupon CEBPAdm cases were shown to be associated with better overall survival (OS). The occurrence and prognostic impact of concomitant molecular mutations in addition to CEBPAdm has not been assessed until now with exception of GATA2 mutations. Here, we investigated a cohort of 95 AML CEBPAdm cases for concomitant mutations. TET2 was found to be most frequently mutated (34·0%) gene, followed by GATA2 (21·0%), WT1 (13·7%), DNMT3A (9·6%), ASXL1 (9·5%), NRAS (8·4%), KRAS (3·2%), IDH1/2 (6·3%), FLT3-internal tandem duplication (6·3%), FLT3-tyrosine kinase domain (2·1%), NPM1 (2·1%), and RUNX1 (1/94). Patients harbouring additional mutations in the TET2 gene showed significantly worse OS than TET2 wild-type cases (P = 0·035), whereas GATA2-mutated patients showed improved OS (P = 0·032). Serial analyses were performed for 39 CEBPAdm cases with concomitant mutations. Here, we observed that CEBPA mutations present the primary pathogenetic event in the majority of cases (76·9%). Further, a distinct gene expression profile (GEP) was confirmed for CEBPAdm versus CEBPAsm or CEBPA wild-type cases while no significant changes in GEP were observed related to additional mutations within the CEBPAdm AML.
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Grossmann
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Haferlach
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Niroshan
authors.initials: N
authors.lastname: Nadarajah
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Fasan
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Weissmann
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Roller
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Eder
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Stopp
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kern
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kohlmann
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D005260:Female; D050989:GATA2 Transcription Factor / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D052138:Genes, Neoplasm / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D000090243:Nucleophosmin; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C000716967:NPM1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D000090243:Nucleophosmin; D049308:Dioxygenases; C541081:TET2 protein, human