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
Department of Haematology, Oncology and Internal Diseases, Medical University and University Hospital, 1A Banacha Str., 02-097 Warsaw, Poland.
Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland.
Blood Cells Mol Dis. 2015 Dec;55(4):284-92. doi: 10.1016/j.bcmd.2015.07.002. Epub 2015 Jul 7.
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.
CEBPA基因座的拷贝数变异（CNV）代表了伴随急性髓系白血病（AML）的一组异质性突变。本研究的目的是根据年龄、细胞学、CD7和分子标志物等生物学数据，对不同的CEBPA突变类别进行特征描述，并确定影响其病因的可能因素。我们在此报告了在262例正常核型AML（NK-AML）患者群体中CEBPA突变体的发生率为12.6%。我们证实，与单一CEBPA突变相比，双突变AML呈现出一致的生物学特征，且大多伴有年轻患者。我们推测，不同CEBPA突变类别的发病机制可能受不同因素影响。详细的序列分析揭示了2至12bp的频繁断点相关微同源性。对CEBPA基因上微同源基序分布的分析表明，突变连接处较长的微同源序列偶然出现的频率相对较低，这表明它们在CEBPA诱变中具有功能作用。此外，对CEBPA转录水平的准确定量显示，双CEBPA突变与高水平的CEBPA表达相关，而单一N端CEBPA突变与低水平的CEBPA表达相关。这可能表明高水平的CEBPA表达和/或CEBPA基因座的可及性有助于B-ZIP框内重复。
