Oncotarget

Research Papers:

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

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 and Mariana Emerenciano _

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Oncotarget. 2016; 7:53064-53073. https://doi.org/10.18632/oncotarget.10590

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Abstract

Bruno Almeida Lopes1, Claus Meyer2, Thayana Conceição Barbosa1, Udo zur Stadt3, Martin Horstmann3,4,5, Nicola C. Venn6, Susan Heatley7,8, Deborah L. White7,8, Rosemary Sutton6, Maria S. Pombo-de-Oliveira1, Rolf Marschalek2, Mariana Emerenciano1

1Pediatric Hematology-Oncology Program, Research Center, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil

2Diagnostic Center of Acute Leukemia/Institute of Pharmaceutical Biology/ZAFES, Goethe-University of Frankfurt, Biocenter, Germany

3Center for Diagnostics, University Medical Center Hamburg Eppendorf, Hamburg, Germany

4Research Institute Children’s Cancer Center, Hamburg, Germany

5Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Children's Cancer Institute, Lowy Cancer Research Centre UNSW, Sydney, New South Wales, Australia

7South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia

8Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia

Correspondence to:

Mariana Emerenciano, email: memerenciano@inca.gov.br

Keywords: acute lymphoblastic leukemia, COBL, IKZF1, RAG, relapse

Received: May 03, 2016     Accepted: June 30, 2016     Published: July 13, 2016

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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