TY  - JOUR
A1  - Almeida Lopes, Bruno
A1  - Meyer, Claus
A1  - Conceição Barbosa, Thayana
A1  - Zur Stadt, Udo
A1  - Horstmann, Martin
A1  - Venn, Nicola C.
A1  - Heatley, Susan
A1  - White, Deborah L.
A1  - Sutton, Rosemary
A1  - Pombo-de-Oliveira, Maria S.
A1  - Marschalek, Rolf
A1  - Emerenciano, Mariana
T1  - COBL is a novel hotspot for IKZF1 deletions in childhood acute lymphoblastic leukemia
T2  - OncoTarget
N2  - 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.
KW  - acute lymphoblastic leukemia
KW  - COBL
KW  - IKZF1
KW  - RAG
KW  - relapse
Y1  - 2016
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/45553
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-455538
SN  - 1949-2553
N1  - All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
VL  - 7
IS  - 33
SP  - 53064
EP  - 53073
PB  - Impact Journals LLC
CY  - [s. l.]
ER  -