title: Gene-expression profiling identifies distinct subclasses of core binding factor acute myeloid leukemia.
abstract: Core binding factor (CBF) leukemias, characterized by either inv(16)/t(16;16) or t(8;21), constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, there exists substantial biologic and clinical heterogeneity within these cytogenetic groups that is not fully reflected by the current classification system. To improve the molecular characterization we profiled gene expression in a large series (n = 93) of AML patients with CBF leukemia [(inv (16), n = 55; t(8;21), n = 38)]. By unsupervised hierarchical clustering we were able to define a subgroup of CBF cases (n = 35) characterized by shorter overall survival times (P = .03). While there was no obvious correlation with fusion gene transcript levels, FLT3 tyrosine kinase domain, KIT, and NRAS mutations, the newly defined inv(16)/t(8;21) subgroup was associated with elevated white blood cell counts and FLT3 internal tandem duplications (P = .011 and P = .026, respectively). Supervised analyses of gene expression suggested alternative cooperating pathways leading to transformation. In the "favorable" CBF leukemias, antiapoptotic mechanisms and deregulated mTOR signaling and, in the newly defined "unfavorable" subgroup, aberrant MAPK signaling and chemotherapy-resistance mechanisms might play a role. While the leukemogenic relevance of these signatures remains to be validated, their existence nevertheless supports a prognostically relevant biologic basis for the heterogeneity observed in CBF leukemia.
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany. lars.bullinger@uniklinik-ulm.de
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Frank G
authors.initials: FG
authors.lastname: Rücker
authors.forename: Stephan
authors.initials: S
authors.lastname: Kurz
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Claudia
authors.initials: C
authors.lastname: Scholl
authors.forename: Sandrine
authors.initials: S
authors.lastname: Sander
authors.forename: Andrea
authors.initials: A
authors.lastname: Corbacioglu
authors.forename: Claudio
authors.initials: C
authors.lastname: Lottaz
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Pollack
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002869:Chromosome Aberrations; D007446:Chromosome Inversion; D016000:Cluster Analysis; D050660:Core Binding Factors / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D015996:Survival Rate; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D050660:Core Binding Factors; C497970:FLT3 protein, human; D019009:Proto-Oncogene Proteins c-kit; D051941:fms-Like Tyrosine Kinase 3