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.