Lenka Hovorková; Lucie Winkowská; Justina Skořepová; Manuela Krumbholz; Adéla Benešová; Václava Polívková; Julia Alten; Michela Bardini; Claus Meyer; Rathana Kim; Toby N Trahair; Emmanuelle Clappier; Sabina Chiaretti; Michelle Henderson; Rosemary Sutton; Lucie Šrámková; Jan Starý; Kateřina Machová Poláková; Rolf Marschalek; Markus Metzler; Giovanni Cazzaniga; Gunnar Cario; Jan Trka; Markéta Žaliová; Jan Zuna | Molecular Cancer | Jul 2024 | IF: 27,7 | doi.
Mgr. Lenka Hovorková, Ph.D., CLIP ＆ Department of Paediatric Haematology and Oncology, Second Faculty od Medicine and Motol University Hospital
Abstract
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.
Keywords: ABL1; Acute lymphoblastic leukemia; BCR; Chronic myeloid leukemia; Genomic breakpoints.
