Distinct pattern of genomic breakpoints in CML and BCR::ABL1-positive ALL: analysis of 971 patients.

Humans Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics Fusion Proteins, bcr-abl / genetics Chromosome Breakpoints Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics Adult Child Male Female High-Throughput Nucleotide Sequencing

ABL1 Acute lymphoblastic leukemia BCR Chronic myeloid leukemia Genomic breakpoints

Journal

Molecular cancer

ISSN: 1476-4598

Titre abrégé: Mol Cancer

Pays: England

ID NLM: 101147698

Informations de publication

Date de publication:
05 Jul 2024

Historique:

received: 07 06 2024

accepted: 28 06 2024

medline: 6 7 2024

pubmed: 6 7 2024

entrez: 5 7 2024

Statut: epublish

Résumé

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. 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. 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. 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.

Sections du résumé

BACKGROUND BACKGROUND

METHODS 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 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 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.

Identifiants

DOI: 10.1186/s12943-024-02053-4 PMID: 38970095

pubmed: 38970095

doi: 10.1186/s12943-024-02053-4

pii: 10.1186/s12943-024-02053-4

doi:

Substances chimiques

Fusion Proteins, bcr-abl EC 2.7.10.2

Types de publication

Journal Article Letter

Langues

eng

Sous-ensembles de citation

Pagination

138

Subventions

Organisme : Czech Health Research Council

ID : NU21-03-00128

Organisme : Charles University

ID : GAUK 327322

Organisme : MH CZ - DRO

ID : IHBT, 00023736

Organisme : Ministry of Health, Czech Republic

ID : 00064203

Organisme : National Institute for Cancer Research

ID : Program EXCELES, ID Project No. LX22NPO5102

Organisme : Cancer Australia

ID : PdCCRS1128727

Informations de copyright

Références

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