Additional genetic aberrations identified in biCEBPA mutant CN-AML. (A) Somatic mutations affected 3 key regulators of hematopoiesis, namely, CEBPA, GATA2, and Ikaros (IKZF1) in 1 CN-AML patient analyzed by exome sequencing (also see Table 1). Chromatograms are shown for both diagnostic AML samples and corresponding follow-up samples at complete remission (REM) from the same patients. (B) Structure of the human GATA2 gene with 5 coding exons is shown in black, and noncoding exons are shown in gray (top). The GATA2 protein structure includes the N- and C-terminal zinc finger domains (ZF1, ZF2) and the nuclear localization signal (NLS; middle). The amino acid sequence of the N-terminal ZF1 domain of GATA2 is detailed with cysteine residues that are responsible for zinc binding are shown in bold (bottom). Fifteen heterozygous missense mutations were detected in coding exon 4 of GATA2 in 13 of 33 biCEBPA patients (overall frequency, 39.4%). All GATA2 mutations clustered in the highly conserved N-terminal zinc finger domain (ZF domain) of GATA2. Positions A318, G320, and G321 were recurrently affected. The ZF1 also is illustrated as polypeptide chain with the amino acids (circles) targeted by mutations in black (bottom). (C) Frequency distribution of additional genetic aberrations in 33 biCEBPA patients. Each box indicates 1 patient. Dark gray boxes are indicative for patients who are positive for the respective mutation; light gray boxes indicate wild-type status. Missing information is shown as a white space. All 33 biCEBPA-mutated patients were NPM1 wild type and did not carry an additional FLT3-TKD or MLL-PTD. FLT3-ITD indicates internal tandem duplications in the FLT3 gene; FLT3-TKD, FLT3 mutations in the tyrosine kinase domain; MLL-PTD, partial tandem duplications in the MLL gene; and NPM1, nucleophosmin.