Commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin-remodeling and splicing

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 non-recurrent, we observed a number 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 non-classical 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 significant enrichment 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.

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Dolnik A, Engelmann JC, Scharfenberger-Schmeer M, Mauch J, Kelkenberg-Schade S, Haldemann B, Fries T, Krönke J, Kühn MW, Paschka P, Kayser S, Wolf S, Gaidzik VI, Schlenk RF, Rücker FG, Döhner H, Lottaz C, Döhner K, Bullinger L