COBL is a novel hotspot for IKZF1 deletions in childhood acute lymphoblastic leukemia
| Autor: | Deborah L. White, Udo zur Stadt, Rosemary Sutton, Claus Meyer, Martin A. Horstmann, Thayana Conceição Barbosa, Rolf Marschalek, Bruno Almeida Lopes, Mariana Emerenciano, Nicola C. Venn, Maria S. Pombo-de-Oliveira, Susan L. Heatley |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Monosomy Adolescent DNA Copy Number Variations Isochromosome Chromosome Breakpoints acute lymphoblastic leukemia Biology COBL 03 medical and health sciences Ikaros Transcription Factor 0302 clinical medicine Sequence Homology Nucleic Acid medicine Humans Multiplex ligation-dependent probe amplification Amino Acid Sequence ddc:610 Childhood Acute Lymphoblastic Leukemia Genetics Chromosome 7 (human) relapse Acute leukemia Base Sequence Sequence Homology Amino Acid Microfilament Proteins Infant Nucleic acid amplification technique RAG Precursor Cell Lymphoblastic Leukemia-Lymphoma medicine.disease IKZF1 Isochromosomes 030104 developmental biology Oncology 030220 oncology & carcinogenesis Child Preschool Female Chromosome Deletion Nucleic Acid Amplification Techniques Chromosomes Human Pair 7 Gene Deletion Research Paper |
| Zdroj: | Oncotarget |
| Popis: | // Bruno Almeida Lopes 1 , Claus Meyer 2 , Thayana Conceicao Barbosa 1 , Udo zur Stadt 3 , Martin Horstmann 3, 4, 5 , Nicola C. Venn 6 , Susan Heatley 7, 8 , Deborah L. White 7, 8 , Rosemary Sutton 6 , Maria S. Pombo-de-Oliveira 1 , Rolf Marschalek 2 , Mariana Emerenciano 1 1 Pediatric Hematology-Oncology Program, Research Center, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil 2 Diagnostic Center of Acute Leukemia/Institute of Pharmaceutical Biology/ZAFES, Goethe-University of Frankfurt, Biocenter, Germany 3 Center for Diagnostics, University Medical Center Hamburg Eppendorf, Hamburg, Germany 4 Research Institute Children’s Cancer Center, Hamburg, Germany 5 Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 6 Children's Cancer Institute, Lowy Cancer Research Centre UNSW, Sydney, New South Wales, Australia 7 South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia 8 Discipline 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 (Δ IKZF1 ) 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 Δ IKZF1 . Since the multiplex PCR was not able to detect complete deletions ( IKZF1 Δ1-8), which account for ~30% of all Δ IKZF1 , 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 Δ IKZF1 . 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 Δ IKZF1 . 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 Δ IKZF1 . |
| Databáze: | OpenAIRE |
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