title: RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group.
abstract: OBJECTIVE
  To evaluate frequency, biologic features, and clinical relevance of RUNX1 mutations in acute myeloid leukemia (AML).
  
  
  METHODS
  Diagnostic samples from 945 patients (age 18 to 60 years) were analyzed for RUNX1 mutations. In a subset of cases (n = 269), microarray gene expression analysis was performed.
  
  
  RESULTS
  Fifty-nine RUNX1 mutations were identified in 53 (5.6%) of 945 cases, predominantly in exons 3 (n = 11), 4 (n = 10), and 8 (n = 23). RUNX1 mutations clustered in the intermediate-risk cytogenetic group (46 of 640, 7.2%; cytogenetically normal, 34 of 538, 6.3%), whereas they were less frequent in adverse-risk cytogenetics (five of 109, 4.6%) and absent in core-binding-factor AML (0 of 77) and acute promyelocytic leukemia (0 of 61). RUNX1 mutations were associated with MLL-partial tandem duplications (P = .0007) and IDH1/IDH2 mutations (P = .03), inversely correlated with NPM1 (P < .0001), and in trend with CEBPA (P = .10) mutations. RUNX1 mutations were characterized by a distinct gene expression pattern; this RUNX1 mutation-derived signature was not exclusive for the mutation, but also included mostly adverse-risk AML [eg, 7q-, -7, inv(3), or t(3;3)]. RUNX1 mutations predicted for resistance to chemotherapy (rates of refractory disease 30% and 19%, P = .047, for RUNX1-mutated and wild-type patients, respectively), as well as inferior event-free survival (EFS; P < .0001), relapse-free survival (RFS, P = .022), and overall survival (P = .051). In multivariable analysis, RUNX1 mutations were an independent prognostic marker for shorter EFS (P = .007). Explorative subgroup analysis revealed that allogeneic hematopoietic stem-cell transplantation had a favorable impact on RFS in RUNX1-mutated patients (P < .0001).
  
  
  CONCLUSIONS
  AML with RUNX1 mutations are characterized by distinct genetic properties and are associated with resistance to therapy and inferior outcome.
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
authors.forename: Verena I
authors.initials: VI
authors.lastname: Gaidzik
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Zimmermann
authors.forename: Jürgen
authors.initials: J
authors.lastname: Röck
authors.forename: Peter
authors.initials: P
authors.lastname: Paschka
authors.forename: Andrea
authors.initials: A
authors.lastname: Corbacioglu
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Daniela
authors.initials: D
authors.lastname: Späth
authors.forename: Andrea
authors.initials: A
authors.lastname: Kündgen
authors.forename: Ingo G H
authors.initials: IG
authors.lastname: Schmidt-Wolf
authors.forename: Katharina
authors.initials: K
authors.lastname: Götze
authors.forename: David
authors.initials: D
authors.lastname: Nachbaur
authors.forename: Michael
authors.initials: M
authors.lastname: Pfreundschuh
authors.forename: Heinz A
authors.initials: HA
authors.lastname: Horst
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
mesh_terms: D000293:Adolescent; D000328:Adult; D001317:Austria; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D020732:Cytogenetic Analysis; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005091:Exons; D005260:Female; D020440:Gene Duplication; D020869:Gene Expression Profiling / Q000379:methods; D005838:Genotype; D005858:Germany; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D015996:Survival Rate; D020080:Tandem Repeat Sequences; D013997:Time Factors; D055815:Young Adult
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C497422:KMT2A protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; C493728:RUNX1 protein, human; D000090243:Nucleophosmin; D051788:Myeloid-Lymphoid Leukemia Protein; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D011495:Histone-Lysine N-Methyltransferase