IKZF1 Deletions with COBL Breakpoints Are Not Driven by RAG-Mediated Recombination Events in Acute Lymphoblastic Leukemia

Lopes, Bruno A., Meyer, Claus, Barbosa, Thayana C., Poubel, Caroline P., Mansur, Marcela B., Duployez, Nicolas, Bashton, Matthew, Harrison, Christine J., zur Stadt, Udo, Horstmann, Martin, Pombo-de-Oliveira, Maria S., Palmi, Chiara, Cazzaniga, Gianni, Venn, Nicola C., Sutton, Rosemary, Alonso, Cristina N., Tsaur, Grigory, Gupta, Sanjeev K., Bakhshi, Sameer, Marschalek, Rolf and Emerenciano, Mariana (2019) IKZF1 Deletions with COBL Breakpoints Are Not Driven by RAG-Mediated Recombination Events in Acute Lymphoblastic Leukemia. Translational Oncology, 12 (5). pp. 726-732. ISSN 1936-5233

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Official URL: https://doi.org/10.1016/j.tranon.2019.02.002

Abstract

IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-ALL with COBL rearrangements (COBL-r). Patients with B-ALL and IKZF1 deletion (n = 133) were included. IKZF1 ∆1-8 were associated with large alterations within chromosome 7: monosomy 7 (18%), isochromosome 7q (10%), 7p loss (19%), and interstitial deletions (53%). The latter included COBL-r, which were found in 12% of the IKZF1 ∆1-8 cohort. Patients with COBL-r are mostly classified as intermediate cytogenetic risk and frequently harbor ETV6, PAX5, CDKN2A/B deletions. Overall, 56% of breakpoints were located within COBL intron 5. Cryptic recombination signal sequence motifs were broadly distributed within the sequence of COBL, and no enrichment for the breakpoint cluster region was found. In summary, a diverse spectrum of alterations characterizes ΔIKZF1 and they also include deletion breakpoints within COBL. We confirmed that COBL is a hotspot associated with ΔIKZF1, but these rearrangements are not driven by RAG-mediated recombination.

Item Type: Article
Subjects: A400 Clinical Dentistry
B900 Others in Subjects allied to Medicine
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Elena Carlaw
Date Deposited: 17 Jan 2020 16:49
Last Modified: 17 Jan 2020 17:00
URI: http://nrl.northumbria.ac.uk/id/eprint/41936

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