COBL is a novel hotspot for IKZF1 deletions in childhood acute lymphoblastic leukemia
Date
2016
Authors
Lopes, B.
Meyer, C.
Barbosa, T.
Stadt, U.
Horstmann, M.
Venn, N.
Heatley, S.
White, D.
Sutton, R.
Pombo-de-Oliveira, M.
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Journal article
Citation
Oncotarget, 2016; 7(33):53064-53073
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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
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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.
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