title: CEBPA copy number variations in normal karyotype acute myeloid leukemia: Possible role of breakpoint-associated microhomology and chromatin status in CEBPA mutagenesis.
abstract: 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.
authors.affiliation: Department of Haematology, Oncology and Internal Diseases, Medical University and University Hospital, 1A Banacha Str., 02-097 Warsaw, Poland. Electronic address: marta.libura@gmail.com.
authors.forename: Marta
authors.initials: M
authors.lastname: Libura
authors.affiliation: Department of Haematology, Oncology and Internal Diseases, Medical University and University Hospital, 1A Banacha Str., 02-097 Warsaw, Poland. Electronic address: m.przest@autograf.pl.
authors.forename: Marta
authors.initials: M
authors.lastname: Pawełczyk
authors.affiliation: Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: iflorek@gmail.com.
authors.forename: Izabella
authors.initials: I
authors.lastname: Florek
authors.affiliation: Department of Clinical Genetics, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 9 Skłodowska-Curie Str., 85-094 Bydgoszcz, Poland. Electronic address: k.matiakowska@cm.umk.pl.
authors.forename: Karolina
authors.initials: K
authors.lastname: Matiakowska
authors.affiliation: Department of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, 4 Pasteura Str., 50-367 Wrocław, Poland. Electronic address: bozena.jazwiec@umed.wroc.pl.
authors.forename: Bożena
authors.initials: B
authors.lastname: Jaźwiec
authors.affiliation: Institute of Haematology and Transfusion Medicine, 14 Gandhi Str., 02-776 Warsaw, Poland. Electronic address: kborg@ihit.waw.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Borg
authors.affiliation: Institute of Haematology and Transfusion Medicine, 14 Gandhi Str., 02-776 Warsaw, Poland. Electronic address: isolarska@ihit.waw.pl.
authors.forename: Iwona
authors.initials: I
authors.lastname: Solarska
authors.affiliation: Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: magdalena_zawada@wp.pl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zawada
authors.affiliation: Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: sdujka@interia.pl.
authors.forename: Sylwia
authors.initials: S
authors.lastname: Czekalska
authors.affiliation: Department of Haematology, Oncology and Internal Diseases, Medical University and University Hospital, 1A Banacha Str., 02-097 Warsaw, Poland. Electronic address: jola2204@gmail.com.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Libura
authors.affiliation: Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: salaman@tlen.pl.
authors.forename: Zoriana
authors.initials: Z
authors.lastname: Salamanczuk
authors.affiliation: Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: jakobcz@tlen.pl.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Jakóbczyk
authors.affiliation: Department of Clinical Genetics, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 9 Skłodowska-Curie Str., 85-094 Bydgoszcz, Poland. Electronic address: basia@cm.umk.pl.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mucha
authors.affiliation: Department of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, 4 Pasteura Str., 50-367 Wrocław, Poland. Electronic address: ewadus@wp.pl.
authors.forename: Ewa
authors.initials: E
authors.lastname: Duszeńko
authors.affiliation: Department of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, 4 Pasteura Str., 50-367 Wrocław, Poland. Electronic address: krysosz@wp.pl.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Soszyńska
authors.affiliation: Department of Haematology, Oncology and Internal Diseases, Medical University and University Hospital, 1A Banacha Str., 02-097 Warsaw, Poland. Electronic address: karolina.karabin@o2.pl.
authors.forename: Karolina
authors.initials: K
authors.lastname: Karabin
authors.affiliation: Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: bjakubas@wp.pl.
authors.forename: Beata
authors.initials: B
authors.lastname: Piątkowska-Jakubas
authors.affiliation: Department of Haematology, Copernicus Hospital, 17/19 Batory Str., 87-100 Toruń, Poland. Electronic address: hematologia@med.torun.pl.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Całbecka
authors.affiliation: Department of Haematology, Copernicus Hospital, 17/19 Batory Str., 87-100 Toruń, Poland. Electronic address: justynag@med.torun.pl.
authors.forename: Justyna
authors.initials: J
authors.lastname: Gajkowska-Kulig
authors.affiliation: Department of Haematology, Dr Biziel University Hospital, 75 Ujejskiego Str., 85-168 Bydgoszcz, Poland. Electronic address: grazyna.gadomska@biziel.pl.
authors.forename: Grażyna
authors.initials: G
authors.lastname: Gadomska
authors.affiliation: Department of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, 4 Pasteura Str., 50-367 Wrocław, Poland. Electronic address: marekkielbik@poczta.onet.pl.
authors.forename: Marek
authors.initials: M
authors.lastname: Kiełbiński
authors.affiliation: Institute of Haematology and Transfusion Medicine, 14 Gandhi Str., 02-776 Warsaw, Poland. Electronic address: aejduk@onet.eu.
authors.forename: Anna
authors.initials: A
authors.lastname: Ejduk
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, 20/24 Francuska str., 40-027 Katowice, Poland. Electronic address: dkata@wpl.pl.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Kata
authors.affiliation: Department of Hematology, SPZOZ ZSM Chorzów, 11 Strzelców Bytomskich Str., 41-500 Chorzów, Poland. Electronic address: sgrosicki@wp.pl.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Grosicki
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, 20/24 Francuska str., 40-027 Katowice, Poland. Electronic address: klinhem@sum.edu.pl.
authors.forename: Sławomira
authors.initials: S
authors.lastname: Kyrcz-Krzemień
authors.affiliation: Institute of Haematology and Transfusion Medicine, 14 Gandhi Str., 02-776 Warsaw, Poland. Electronic address: sekihit@ihit.waw.pl.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Warzocha
authors.affiliation: Department of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, 4 Pasteura Str., 50-367 Wrocław, Poland. Electronic address: kuliczk@hemat.am.wroc.pl.
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Kuliczkowski
authors.affiliation: Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: alekskot@cm-uj.krakow.pl.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Skotnicki
authors.affiliation: Department of Haematology, Oncology and Internal Diseases, Medical University and University Hospital, 1A Banacha Str., 02-097 Warsaw, Poland. Electronic address: wiktor@amwaw.edu.pl.
authors.forename: Wiesław Wiktor
authors.initials: WW
authors.lastname: Jęrzejczak
authors.affiliation: Department of Clinical Genetics, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 9 Skłodowska-Curie Str., 85-094 Bydgoszcz, Poland; Department of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, 4 Pasteura Str., 50-367 Wrocław, Poland. Electronic address: haus@cm.umk.pl.
authors.forename: Olga
authors.initials: O
authors.lastname: Haus
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D002843:Chromatin / Q000235:genetics; D056905:Chromosome Breakpoints; D019295:Computational Biology / Q000379:methods; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D056426:Genetic Loci; D006801:Humans; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016296:Mutagenesis; D009154:Mutation; D059372:Nucleotide Motifs; D012333:RNA, Messenger / Q000235:genetics; D055815:Young Adult
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D002843:Chromatin; D012333:RNA, Messenger
keywords: Acute myeloid leukemia; CEBPA; Direct repeats; Microhomology motifs