title: Risk assessment in patients with acute myeloid leukemia and a normal karyotype.
abstract: OBJECTIVE
  The recognition of a number of leukemia-specific cytogenetic abnormalities and their role as independent prognostic factors have provided considerable insights into leukemia pathogenesis and have paved the way to adopt risk-adapted treatment. However, approximately 50% of newly diagnosed acute myeloid leukemia (AML) have a normal karyotype. There has therefore been much interest in identifying molecular markers that could help to improve the prognostic stratification of patients with normal-karyotype AML.
  
  
  METHODS
  Consecutive untreated AML patients (n = 67) from a single institution all with normal karyotype were analyzed for the presence of mutations in the myeloid transcription factor gene CEBPA (for CCAAT/enhancer binding protein-alpha), for internal tandem duplications (ITD) of the tyrosine kinase receptor gene FLT3 (for fms-like tyrosine kinase 3), and for expression of the BAALC gene (for brain and acute leukemia, cytoplasmic).
  
  
  RESULTS
  17.9% of normal-karyotype AML had mutations in the CEBPA gene, and 28.4% had FLT3-ITD; 65.7% (44 of 67) had high BAALC expression and 34.3% (23 of 67) had low BAALC expression. Patients with CEBPA mutations had a very favorable course of their disease. Median disease-free survival (DFS) and overall survival (OS) were 33.5 and 45.5 months, respectively, compared with 10 (e.g., 12 months in patients without CEBPA mutations; P = 0.0017; P = 0.0007). AML patients with FLT3-ITD had significantly shorter median DFS (P = 0.0328) and OS (P = 0.0148) than patients without FLT3-ITD. High BAALC expression predicted for a shorter DFS (P = 0.0152) and OS (P = 0.0210) compared with AML with low BAALC expression; 53.7% of normal-karyotype AML had neither FLT3-ITD nor CEBPA mutations. We found that high BAALC expression in normal-karyotype AML with neither FLT3-ITD nor CEBPA mutations (18 of 67) indicates adverse prognosis for both DFS and OS (P = 0.0001; e.g., P = 0.0001) compared with the group with low BAALC expression and absent FLT3-ITD and CEBPA mutations (18 of 67). Thus, BAALC expression represents a novel prognostic marker particularly for normal-karyotype AML patients with neither FLT3-ITD nor CEBPA mutations.
  
  
  CONCLUSIONS
  Assessment of CEBPA mutations, FLT3-ITD, and BAALC expression permits to split normal-karyotype AML into clinically distinct subgroups.
authors.affiliation: Institute of Medical Oncology and the Laboratory for Molecular Diagnostics, Department of Hematology, University of Berne, CH-3010 Berne, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Bienz
authors.forename: Madleina
authors.initials: M
authors.lastname: Ludwig
authors.forename: Elisabeth Oppliger
authors.initials: EO
authors.lastname: Leibundgut
authors.forename: Beatrice U
authors.initials: BU
authors.lastname: Mueller
authors.forename: Daniel
authors.initials: D
authors.lastname: Ratschiller
authors.forename: Max
authors.initials: M
authors.lastname: Solenthaler
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fey
authors.forename: Thomas
authors.initials: T
authors.lastname: Pabst
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016130:Immunophenotyping; D007621:Karyotyping; D007951:Leukemia, Myeloid / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D018570:Risk Assessment / Q000379:methods; D016019:Survival Analysis; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D015703:Antigens, CD; C442828:BAALC protein, human; D022763:CCAAT-Enhancer-Binding Protein-alpha; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3