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

Marta Libura¹, Marta Pawełczyk², Izabella Florek³, Karolina Matiakowska⁴, Bożena Jaźwiec⁵, Katarzyna Borg⁶, Iwona Solarska⁷, Magdalena Zawada⁸, Sylwia Czekalska⁹, Jolanta Libura¹⁰, Zoriana Salamanczuk¹¹, Małgorzata Jakóbczyk¹², Barbara Mucha¹³, Ewa Duszeńko¹⁴, Krystyna Soszyńska¹⁵, Karolina Karabin¹⁶, Beata Piątkowska-Jakubas¹⁷, Małgorzata Całbecka¹⁸, Justyna Gajkowska-Kulig¹⁹, Grażyna Gadomska²⁰, Marek Kiełbiński²¹, Anna Ejduk²², Dariusz Kata²³, Sebastian Grosicki²⁴, Sławomira Kyrcz-Krzemień²⁵, Krzysztof Warzocha²⁶, Kazimierz Kuliczkowski²⁷, Aleksander Skotnicki²⁸, Wiesław Wiktor Jęrzejczak²⁹, Olga Haus³⁰

Affiliations

¹ 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.
² 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.
³ Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: iflorek@gmail.com.
⁴ 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.
⁵ 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.
⁶ Institute of Haematology and Transfusion Medicine, 14 Gandhi Str., 02-776 Warsaw, Poland. Electronic address: kborg@ihit.waw.pl.
⁷ Institute of Haematology and Transfusion Medicine, 14 Gandhi Str., 02-776 Warsaw, Poland. Electronic address: isolarska@ihit.waw.pl.
⁸ Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: magdalena_zawada@wp.pl.
⁹ Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: sdujka@interia.pl.
¹⁰ Department of Haematology, Oncology and Internal Diseases, Medical University and University Hospital, 1A Banacha Str., 02-097 Warsaw, Poland. Electronic address: jola2204@gmail.com.
¹¹ Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: salaman@tlen.pl.
¹² Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: jakobcz@tlen.pl.
¹³ 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.
¹⁴ Department of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, 4 Pasteura Str., 50-367 Wrocław, Poland. Electronic address: ewadus@wp.pl.
¹⁵ Department of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, 4 Pasteura Str., 50-367 Wrocław, Poland. Electronic address: krysosz@wp.pl.
¹⁶ 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.
¹⁷ Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: bjakubas@wp.pl.
¹⁸ Department of Haematology, Copernicus Hospital, 17/19 Batory Str., 87-100 Toruń, Poland. Electronic address: hematologia@med.torun.pl.
¹⁹ Department of Haematology, Copernicus Hospital, 17/19 Batory Str., 87-100 Toruń, Poland. Electronic address: justynag@med.torun.pl.
²⁰ Department of Haematology, Dr Biziel University Hospital, 75 Ujejskiego Str., 85-168 Bydgoszcz, Poland. Electronic address: grazyna.gadomska@biziel.pl.
²¹ Department of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, 4 Pasteura Str., 50-367 Wrocław, Poland. Electronic address: marekkielbik@poczta.onet.pl.
²² Institute of Haematology and Transfusion Medicine, 14 Gandhi Str., 02-776 Warsaw, Poland. Electronic address: aejduk@onet.eu.
²³ Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, 20/24 Francuska str., 40-027 Katowice, Poland. Electronic address: dkata@wpl.pl.
²⁴ Department of Hematology, SPZOZ ZSM Chorzów, 11 Strzelców Bytomskich Str., 41-500 Chorzów, Poland. Electronic address: sgrosicki@wp.pl.
²⁵ 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.
²⁶ Institute of Haematology and Transfusion Medicine, 14 Gandhi Str., 02-776 Warsaw, Poland. Electronic address: sekihit@ihit.waw.pl.
²⁷ 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.
²⁸ Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: alekskot@cm-uj.krakow.pl.
²⁹ 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.
³⁰ 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.

PMID: 26460249
DOI: 10.1016/j.bcmd.2015.07.002

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

Marta Libura et al. Blood Cells Mol Dis. 2015 Dec.

. 2015 Dec;55(4):284-92.

doi: 10.1016/j.bcmd.2015.07.002. Epub 2015 Jul 7.

Authors

Affiliations

¹ 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.
² 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.
³ Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: iflorek@gmail.com.
⁴ 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.
⁵ 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.
⁶ Institute of Haematology and Transfusion Medicine, 14 Gandhi Str., 02-776 Warsaw, Poland. Electronic address: kborg@ihit.waw.pl.
⁷ Institute of Haematology and Transfusion Medicine, 14 Gandhi Str., 02-776 Warsaw, Poland. Electronic address: isolarska@ihit.waw.pl.
⁸ Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: magdalena_zawada@wp.pl.
⁹ Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: sdujka@interia.pl.
¹⁰ Department of Haematology, Oncology and Internal Diseases, Medical University and University Hospital, 1A Banacha Str., 02-097 Warsaw, Poland. Electronic address: jola2204@gmail.com.
¹¹ Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: salaman@tlen.pl.
¹² Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: jakobcz@tlen.pl.
¹³ 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.
¹⁴ Department of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, 4 Pasteura Str., 50-367 Wrocław, Poland. Electronic address: ewadus@wp.pl.
¹⁵ Department of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, 4 Pasteura Str., 50-367 Wrocław, Poland. Electronic address: krysosz@wp.pl.
¹⁶ 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.
¹⁷ Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: bjakubas@wp.pl.
¹⁸ Department of Haematology, Copernicus Hospital, 17/19 Batory Str., 87-100 Toruń, Poland. Electronic address: hematologia@med.torun.pl.
¹⁹ Department of Haematology, Copernicus Hospital, 17/19 Batory Str., 87-100 Toruń, Poland. Electronic address: justynag@med.torun.pl.
²⁰ Department of Haematology, Dr Biziel University Hospital, 75 Ujejskiego Str., 85-168 Bydgoszcz, Poland. Electronic address: grazyna.gadomska@biziel.pl.
²¹ Department of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, 4 Pasteura Str., 50-367 Wrocław, Poland. Electronic address: marekkielbik@poczta.onet.pl.
²² Institute of Haematology and Transfusion Medicine, 14 Gandhi Str., 02-776 Warsaw, Poland. Electronic address: aejduk@onet.eu.
²³ Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, 20/24 Francuska str., 40-027 Katowice, Poland. Electronic address: dkata@wpl.pl.
²⁴ Department of Hematology, SPZOZ ZSM Chorzów, 11 Strzelców Bytomskich Str., 41-500 Chorzów, Poland. Electronic address: sgrosicki@wp.pl.
²⁵ 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.
²⁶ Institute of Haematology and Transfusion Medicine, 14 Gandhi Str., 02-776 Warsaw, Poland. Electronic address: sekihit@ihit.waw.pl.
²⁷ 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.
²⁸ Department of Haematology, Faculty of Medicine Jagiellonian University, 19 Kopernika Str., 31-501 Cracow, Poland. Electronic address: alekskot@cm-uj.krakow.pl.
²⁹ 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.
³⁰ 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.

PMID: 26460249
DOI: 10.1016/j.bcmd.2015.07.002

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.

Keywords: Acute myeloid leukemia; CEBPA; Direct repeats; Microhomology motifs.

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

Affiliations

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

Authors

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Abstract

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LinkOut - more resources

Full Text Sources

Medical