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Distinct pattern of genomic breakpoints in CML and BCR::ABL1-positive ALL: analysis of 971 patients
L. Hovorkova, L. Winkowska, J. Skorepova, M. Krumbholz, A. Benesova, V. Polivkova, J. Alten, M. Bardini, C. Meyer, R. Kim, TN. Trahair, E. Clappier, S. Chiaretti, M. Henderson, R. Sutton, L. Sramkova, J. Stary, KM. Polakova, R. Marschalek, M....
Language English Country England, Great Britain
Document type Letter
Grant support
NU21-03-00128
Czech Health Research Council
GAUK 327322
Charles University
IHBT, 00023736
MH CZ - DRO
00064203
Ministry of Health, Czech Republic
Program EXCELES, ID Project No. LX22NPO5102
National Institute for Cancer Research
PdCCRS1128727
Cancer Australia
NLK
BioMedCentral
from 2002-12-01
BioMedCentral Open Access
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Directory of Open Access Journals
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Free Medical Journals
from 2002
PubMed Central
from 2002
Europe PubMed Central
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ProQuest Central
from 2009-01-01
Open Access Digital Library
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Open Access Digital Library
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Open Access Digital Library
from 2002-07-01
Medline Complete (EBSCOhost)
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ROAD: Directory of Open Access Scholarly Resources
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Springer Nature OA/Free Journals
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- MeSH
- Precursor Cell Lymphoblastic Leukemia-Lymphoma * genetics pathology MeSH
- Fusion Proteins, bcr-abl * genetics MeSH
- Chromosome Breakpoints * MeSH
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive * genetics pathology MeSH
- Child MeSH
- Adult MeSH
- Humans MeSH
- High-Throughput Nucleotide Sequencing MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Letter MeSH
BACKGROUND: The BCR::ABL1 is a hallmark of chronic myeloid leukemia (CML) and is also found in acute lymphoblastic leukemia (ALL). Most genomic breaks on the BCR side occur in two regions - Major and minor - leading to p210 and p190 fusion proteins, respectively. METHODS: By multiplex long-distance PCR or next-generation sequencing technology we characterized the BCR::ABL1 genomic fusion in 971 patients (adults and children, with CML and ALL: pediatric ALL: n = 353; pediatric CML: n = 197; adult ALL: n = 166; adult CML: n = 255 patients) and designed "Break-App" web tool to allow visualization and various analyses of the breakpoints. Pearson's Chi-Squared test, Kolmogorov-Smirnov test and logistic regression were used for statistical analyses. RESULTS: Detailed analysis showed a non-random distribution of breaks in both BCR regions, whereas ABL1 breaks were distributed more evenly. However, we found a significant difference in the distribution of breaks between CML and ALL. We found no association of breakpoints with any type of interspersed repeats or DNA motifs. With a few exceptions, the primary structure of the fusions suggests non-homologous end joining being responsible for the BCR and ABL1 gene fusions. Analysis of reciprocal ABL1::BCR fusions in 453 patients showed mostly balanced translocations without major deletions or duplications. CONCLUSIONS: Taken together, our data suggest that physical colocalization and chromatin accessibility, which change with the developmental stage of the cell (hence the difference between ALL and CML), are more critical factors influencing breakpoint localization than presence of specific DNA motifs.
Children's Cancer Institute Randwick Australia
CLIP Childhood Leukaemia Investigation Prague Prague Czech Republic
Department of Pediatrics University Hospital Schleswig Holstein Kiel Germany
Hematology laboratory AP HP Saint Louis hospital Université Paris Cité Paris France
Institute of Hematology and Blood Transfusion Prague Czech Republic
Kids Cancer Centre Sydney Children's Hospital Randwick Sydney Australia
Medical Genetics School of Medicine and Surgery Univ Milano Bicocca Monza Italy
School of Women's and Children's Health School of Medicine University of NSW Sydney Australia
Tettamanti Center Fondazione IRCCS San Gerardo dei Tintori Monza Italy
References provided by Crossref.org
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