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https://hdl.handle.net/2440/103894
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Type: | Journal article |
Title: | COBL is a novel hotspot for IKZF1 deletions in childhood acute lymphoblastic leukemia |
Author: | Lopes, B. Meyer, C. Barbosa, T. Stadt, U. Horstmann, M. Venn, N. Heatley, S. White, D. Sutton, R. Pombo-de-Oliveira, M. Marschalek, R. Emerenciano, M. |
Citation: | Oncotarget, 2016; 7(33):53064-53073 |
Publisher: | Impact Journals |
Issue Date: | 2016 |
ISSN: | 1949-2553 1949-2553 |
Statement of Responsibility: | 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-Oliveira, Rolf Marschalek, Mariana Emerenciano |
Abstract: | 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. |
Keywords: | Acute lymphoblastic leukemia; COBL; IKZF1; RAG; relapse |
Rights: | Copyright status unknown |
DOI: | 10.18632/oncotarget.10590 |
Grant ID: | NHMRC |
Published version: | http://dx.doi.org/10.18632/oncotarget.10590 |
Appears in Collections: | Aurora harvest 7 Medicine publications |
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