title: Commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin remodeling and splicing.
abstract: Acute myeloid leukemia (AML) is characterized by molecular heterogeneity. As commonly altered genomic regions point to candidate genes involved in leukemogenesis, we used microarray-based comparative genomic hybridization and single nucleotide polymorphism profiling data of 391 AML cases to further narrow down genomic regions of interest. Targeted resequencing of 1000 genes located in the critical regions was performed in a representative cohort of 50 AML samples comprising all major cytogenetic subgroups. We identified 120 missense/nonsense mutations as well as 60 insertions/deletions affecting 73 different genes (∼ 3.6 tumor-specific aberrations/AML). While most of the newly identified alterations were nonrecurrent, we observed an enrichment of mutations affecting genes involved in epigenetic regulation including known candidates like TET2, TET1, DNMT3A, and DNMT1, as well as mutations in the histone methyltransferases NSD1, EZH2, and MLL3. Furthermore, we found mutations in the splicing factor SFPQ and in the nonclassic regulators of mRNA processing CTCF and RAD21. These splicing-related mutations affected 10% of AML patients in a mutually exclusive manner. In conclusion, we could identify a large number of alterations in genes involved in aberrant splicing and epigenetic regulation in genomic regions commonly altered in AML, highlighting their important role in the molecular pathogenesis of AML.
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Dolnik
authors.forename: Julia C
authors.initials: JC
authors.lastname: Engelmann
authors.forename: Maren
authors.initials: M
authors.lastname: Scharfenberger-Schmeer
authors.forename: Julian
authors.initials: J
authors.lastname: Mauch
authors.forename: Sabine
authors.initials: S
authors.lastname: Kelkenberg-Schade
authors.forename: Berit
authors.initials: B
authors.lastname: Haldemann
authors.forename: Tamara
authors.initials: T
authors.lastname: Fries
authors.forename: Jan
authors.initials: J
authors.lastname: Krönke
authors.forename: Michael W M
authors.initials: MW
authors.lastname: Kühn
authors.forename: Peter
authors.initials: P
authors.lastname: Paschka
authors.forename: Sabine
authors.initials: S
authors.lastname: Kayser
authors.forename: Stephan
authors.initials: S
authors.lastname: Wolf
authors.forename: Verena I
authors.initials: VI
authors.lastname: Gaidzik
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Frank G
authors.initials: FG
authors.lastname: Rücker
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Claudio
authors.initials: C
authors.lastname: Lottaz
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
mesh_terms: D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D012326:RNA Splicing / Q000235:genetics*