CEBPA copy number variations in normal karyotype acute myeloid leukemia: Possible role of breakpoint-associated microhomology and chromatin status in CEBPA mutagenesis

• Published in: Blood cells, molecules, & diseases Vol. 55; no. 4; pp. 284 - 292
• Main Authors: Libura, Marta, Pawełczyk, Marta, Florek, Izabella, Matiakowska, Karolina, Jaźwiec, Bożena, Borg, Katarzyna, Solarska, Iwona, Zawada, Magdalena, Czekalska, Sylwia, Libura, Jolanta, Salamanczuk, Zoriana, Jakóbczyk, Małgorzata, Mucha, Barbara, Duszeńko, Ewa, Soszyńska, Krystyna, Karabin, Karolina, Piątkowska-Jakubas, Beata, Całbecka, Małgorzata, Gajkowska-Kulig, Justyna, Gadomska, Grażyna, Kiełbiński, Marek, Ejduk, Anna, Kata, Dariusz, Grosicki, Sebastian, Kyrcz-Krzemień, Sławomira, Warzocha, Krzysztof, Kuliczkowski, Kazimierz, Skotnicki, Aleksander, Jęrzejczak, Wiesław Wiktor, Haus, Olga
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2015
• Subjects: Acute myeloid leukemia; Adolescent; Adult; Aged; Aged, 80 and over; Base Sequence; CCAAT-Enhancer-Binding Proteins - genetics; CEBPA; Chromatin - genetics; Chromosome Breakpoints; Computational Biology - methods; Direct repeats; DNA Copy Number Variations; DNA Mutational Analysis; Female; Gene Expression Regulation, Leukemic; Genetic Loci; Humans; Karyotype; Leukemia, Myeloid, Acute - diagnosis; Leukemia, Myeloid, Acute - genetics; Male; Microhomology motifs; Middle Aged; Mutagenesis; Mutation; Nucleotide Motifs; RNA, Messenger - genetics; Young Adult; CEBPA; Microhomology motifs; Direct repeats; Acute myeloid leukemia
• ISSN: 1079-9796; 1096-0961
• DOI: 10.1016/j.bcmd.2015.07.002

Copy number variations (CNV) in CEBPA locus represent heterogeneous group of mutations accompanying acute myeloid leukemia (AML). The aim of this study was to characterize different CEBPA mutation categories in regard to biological data like age, cytology, CD7, and molecular markers, and identify possible factors affecting their etiology. We report here the incidence of 12.6% of CEBPA mutants in the population of 262 normal karyotype AML (NK-AML) patients. We confirmed that double mutant AMLs presented uniform biological features when compared to single CEBPA mutations and accompanied mostly younger patients. We hypothesized that pathogenesis of distinct CEBPA mutation categories might be influenced by different factors. The detailed sequence analysis revealed frequent breakpoint-associated microhomologies of 2 to 12bp. The analysis of distribution of microhomology motifs along CEBPA gene showed that longer stretches of microhomology at the mutational junctions were relatively rare by chance which suggests their functional role in the CEBPA mutagenesis. Additionally, accurate quantification of CEBPA transcript levels showed that double CEBPA mutations correlated with high-level CEBPA expression, whereas single N-terminal CEBPA mutations were associated with low-level CEBPA expression. This might suggest that high-level CEBPA expression and/or accessibility of CEBPA locus contribute to B-ZIP in-frame duplications.