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COBL is a novel hotspot for IKZF1 deletions in childhood acute lymphoblastic leukemia

  • IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in childhood B-cell precursor acute lymphoblastic leukemia. Because of its clinical importance, we previously mapped breakpoints of intragenic deletions and developed a multiplex PCR assay to detect recurrent intragenic ΔIKZF1. Since the multiplex PCR was not able to detect complete deletions (IKZF1 Δ1-8), which account for ~30% of all ΔIKZF1, we aimed at investigating the genomic scenery of IKZF1 Δ1-8. Six samples of cases with IKZF1 Δ1-8 were analyzed by microarray assay, which identified monosomy 7, isochromosome 7q, and large interstitial deletions presenting breakpoints within COBL gene. Then, we established a multiplex ligation-probe amplification (MLPA) assay and screened copy number alterations within chromosome 7 in 43 diagnostic samples with IKZF1 Δ1-8. Our results revealed that monosomy and large interstitial deletions within chromosome 7 are the main causes of IKZF1 Δ1-8. Detailed analysis using long distance inverse PCR showed that six patients (16%) had large interstitial deletions starting within intronic regions of COBL at diagnosis, which is ~611 Kb downstream of IKZF1, suggesting that COBL is a hotspot for ΔIKZF1. We also investigated a series of 25 intragenic deletions (Δ2–8, Δ3–8 or Δ4–8) and 24 relapsed samples, and found one IKZF1-COBL tail-to-tail fusion, thus supporting that COBL is a novel hotspot for ΔIKZF1. Finally, using RIC score methodology, we show that breakpoint sequences of IKZF1 Δ1-8 are not analog to RAG-recognition sites, suggesting a different mechanism of error promotion than that suggested for intragenic ΔIKZF1.
Metadaten
Author:Bruno Almeida Lopes, Claus Meyer, Thayana Conceição Barbosa, Udo Zur Stadt, Martin Horstmann, Nicola C. Venn, Susan Heatley, Deborah L. White, Rosemary Sutton, Maria S. Pombo-de-OliveiraORCiD, Rolf MarschalekORCiDGND, Mariana Emerenciano
URN:urn:nbn:de:hebis:30:3-455538
DOI:https://doi.org/10.18632/oncotarget.10590
ISSN:1949-2553
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/27419633
Parent Title (English):OncoTarget
Publisher:Impact Journals LLC
Place of publication:[s. l.]
Document Type:Article
Language:English
Year of Completion:2016
Date of first Publication:2016/07/13
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/01/25
Tag:COBL; IKZF1; RAG; acute lymphoblastic leukemia; relapse
Volume:7
Issue:33
Page Number:10
First Page:53064
Last Page:53073
Note:
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HeBIS-PPN:426121430
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 3.0