title: Deregulated expression of EVI1 defines a poor prognostic subset of MLL-rearranged acute myeloid leukemias: a study of the German-Austrian Acute Myeloid Leukemia Study Group and the Dutch-Belgian-Swiss HOVON/SAKK Cooperative Group.
abstract: OBJECTIVE
  To evaluate the prognostic value of ecotropic viral integration 1 gene (EVI1) overexpression in acute myeloid leukemia (AML) with MLL gene rearrangements.
  
  
  METHODS
  We identified 286 patients with AML with t(11q23) enrolled onto German-Austrian Acute Myeloid Leukemia Study Group and Dutch-Belgian-Swiss Hemato-Oncology Cooperative Group prospective treatment trials. Material was available from 177 AML patients for EVI1 expression analysis.
  
  
  RESULTS
  We divided 286 MLL-rearranged AMLs into three subgroups: t(9;11)(p22;q23) (44.8%), t(6;11)(q27;q23) (14.7%), and t(v;11q23) (40.5%). EVI1 overexpression (EVI1(+)) was found in 45.8% of all patients with t(11q23), with t(6;11) showing the highest frequency (83.9%), followed by t(9;11) at 40.0%, and t(v;11q23) at 34.8%. Concurrent gene mutations were rare or absent in all three subgroups. Within all t(11q23) AMLs, EVI1(+) was the sole prognostic factor, predicting for inferior overall survival (OS; hazard ratio [HR], 2.06; P = .003), relapse-free survival (HR, 2.28; P = .002), and event-free survival (HR, 1.79; P = .009). EVI1(+) AMLs with t(11q23) in first complete remission (CR) had a significantly better outcome after allogeneic transplantation compared with other consolidation therapies (5-year OS, 54.7% v 0%; Mantel-Byar, P = .0006). EVI1(-) t(9;11) AMLs had lower WBC counts, more commonly FAB M5 morphology, and frequently had additional trisomy 8 (39.6%; P < .001). Among t(9;11) AMLs, EVI1(+) again was the sole independent adverse prognostic factor for survival.
  
  
  CONCLUSIONS
  Deregulated EVI1 expression defines poor prognostic subsets among AML with t(11q23) and AML with t(9;11)(p22;q23). Patients with EVI1(+) MLL-rearranged AML seem to benefit from allogeneic transplantation in first CR.
authors.affiliation: University Hospital Ulm, Ulm, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gröschel
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Jan
authors.initials: J
authors.lastname: Engelmann
authors.forename: Veronika
authors.initials: V
authors.lastname: Rockova
authors.forename: Veronica
authors.initials: V
authors.lastname: Teleanu
authors.forename: Michael W M
authors.initials: MW
authors.lastname: Kühn
authors.forename: Karina
authors.initials: K
authors.lastname: Eiwen
authors.forename: Claudia
authors.initials: C
authors.lastname: Erpelinck
authors.forename: Marije
authors.initials: M
authors.lastname: Havermans
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
authors.forename: Ulrich
authors.initials: U
authors.lastname: Germing
authors.forename: Ingo G H
authors.initials: IG
authors.lastname: Schmidt-Wolf
authors.forename: H Berna
authors.initials: HB
authors.lastname: Beverloo
authors.forename: Gerrit J
authors.initials: GJ
authors.lastname: Schuurhuis
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Leo F
authors.initials: LF
authors.lastname: Verdonck
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
authors.forename: Gregor
authors.initials: G
authors.lastname: Verhoef
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.forename: Thomas
authors.initials: T
authors.lastname: Pabst
authors.forename: Mario
authors.initials: M
authors.lastname: Bargetzi
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002869:Chromosome Aberrations; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000235:genetics / Q000401:mortality*; D000074008:MDS1 and EVI1 Complex Locus Protein; D008297:Male; D008875:Middle Aged; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D011519:Proto-Oncogenes / Q000235:genetics*; D012074:Remission Induction; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase