IKZF1 deletions with COBL breakpoints are not driven by RAG-mediated recombination events in acute lymphoblastic leukemia

  • 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.
Author:Bruno Almeida Lopes, Claus Meyer, Thayana Conceição Barbosa, Caroline P. Poubel, Marcela Braga Mansur, Nicolas Duployez, Matthew Bashton, Christine J. Harrison, Udo Zur Stadt, Martin Horstmann, Maria S. Pombo-de-OliveiraORCiD, Chiara Palmi, Gianni Cazzaniga, Nicola C. Venn, Rosemary Sutton, Cristina N. Alonso, Grigory Tsaur, Sanjeev Gupta, Sameer Bakhshi, Rolf MarschalekORCiDGND, Mariana Emerenciano
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/30877974
Parent Title (English):Translational oncology
Publisher:[Neoplasia Press Inc.]
Place of publication:Ann Arbor, Mich.
Document Type:Article
Year of Completion:2019
Date of first Publication:2019/03/13
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/03/28
Page Number:7
First Page:726
Last Page:732
Under a Creative Commons license
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0