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

详细信息    查看全文

• 作者：Marta Libura^a ; ^{marta.libura@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Marta Pawe艂czyk^a ; ^{m.przest@autograf.pl" class="auth_mail" title="E-mail the corresponding author} ; Izabella Florek^b ; ^{iflorek@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Karolina Matiakowska^c ; ^{k.matiakowska@cm.umk.pl" class="auth_mail" title="E-mail the corresponding author} ; Bo偶ena Ja藕wiec^d ; ^{bozena.jazwiec@umed.wroc.pl" class="auth_mail" title="E-mail the corresponding author} ; Katarzyna Borg^e ; ^{kborg@ihit.waw.pl" class="auth_mail" title="E-mail the corresponding author} ; Iwona Solarska^e ; ^{isolarska@ihit.waw.pl" class="auth_mail" title="E-mail the corresponding author} ; Magdalena Zawada^b ; ^{magdalena_zawada@wp.pl" class="auth_mail" title="E-mail the corresponding author} ; Sylwia Czekalska^b ; ^{sdujka@interia.pl" class="auth_mail" title="E-mail the corresponding author} ; Jolanta Libura^a ; ^{jola2204@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Zoriana Salamanczuk^b ; ^{salaman@tlen.pl" class="auth_mail" title="E-mail the corresponding author} ; Ma艂gorzata Jakó ; bczyk^b ; ^{jakobcz@tlen.pl" class="auth_mail" title="E-mail the corresponding author} ; Barbara Mucha^c ; ^{basia@cm.umk.pl" class="auth_mail" title="E-mail the corresponding author} ; Ewa Dusze艅ko^d ; ^{ewadus@wp.pl" class="auth_mail" title="E-mail the corresponding author} ; Krystyna Soszy艅ska^d ; ^{krysosz@wp.pl" class="auth_mail" title="E-mail the corresponding author} ; Karolina Karabin^a ; ^{karolina.karabin@o2.pl" class="auth_mail" title="E-mail the corresponding author} ; Beata Pi膮tkowska-Jakubas^b ; ^{bjakubas@wp.pl" class="auth_mail" title="E-mail the corresponding author} ; Ma艂gorzata Ca艂becka^f ; ^{hematologia@med.torun.pl" class="auth_mail" title="E-mail the corresponding author} ; Justyna Gajkowska-Kulig^f ; ^{justynag@med.torun.pl" class="auth_mail" title="E-mail the corresponding author} ; Gra偶yna Gadomska^g ; ^{grazyna.gadomska@biziel.pl" class="auth_mail" title="E-mail the corresponding author} ; Marek Kie艂bi艅ski^d ; ^{marekkielbik@poczta.onet.pl" class="auth_mail" title="E-mail the corresponding author} ; Anna Ejduk^e ; ^{aejduk@onet.eu" class="auth_mail" title="E-mail the corresponding author} ; Dariusz Kata^h ; ^{dkata@wpl.pl" class="auth_mail" title="E-mail the corresponding author} ; Sebastian Grosickiⁱ ; ^{sgrosicki@wp.pl" class="auth_mail" title="E-mail the corresponding author} ; S艂awomira Kyrcz-Krzemie艅^h ; ^{klinhem@sum.edu.pl" class="auth_mail" title="E-mail the corresponding author} ; Krzysztof Warzocha^e ; ^{sekihit@ihit.waw.pl" class="auth_mail" title="E-mail the corresponding author} ; Kazimierz Kuliczkowski^d ; ^{kuliczk@hemat.am.wroc.pl" class="auth_mail" title="E-mail the corresponding author} ; Aleksander Skotnicki^b ; ^{alekskot@cm-uj.krakow.pl" class="auth_mail" title="E-mail the corresponding author} ; Wies艂aw Wiktor J臋rzejczak^a ; ^{wiktor@amwaw.edu.pl" class="auth_mail" title="E-mail the corresponding author} ; Olga Haus^c ; ^d ; ^{haus@cm.umk.pl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Acute myeloid leukemia ; CEBPA ; Microhomology motifs ; Direct repeats
• 刊名：Blood Cells, Molecules and Diseases
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：55
• 期：4
• 页码：284-292
• 全文大小：725 K

文摘

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 12 bp. 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.