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

ABSTRACT: IKZF1 deletion (?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 ?IKZF1. Since the multiplex PCR was not able to detect complete deletions (IKZF1 ?1-8), which account for ~30% of all ?IKZF1, we aimed at investigating the genomic scenery of IKZF1 ?1-8. Six samples of cases with IKZF1 ?1-8 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 ?1-8. Our results revealed that monosomy and large interstitial deletions within chromosome 7 are the main causes of IKZF1 ?1-8. 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 ?IKZF1. We also investigated a series of 25 intragenic deletions (?2-8, ?3-8 or ?4-8) and 24 relapsed samples, and found one IKZF1-COBL tail-to-tail fusion, thus supporting that COBL is a novel hotspot for ?IKZF1. Finally, using RIC score methodology, we show that breakpoint sequences of IKZF1 ?1-8 are not analog to RAG-recognition sites, suggesting a different mechanism of error promotion than that suggested for intragenic ?IKZF1.

SUBMITTER: Lopes BA 

PROVIDER: S-EPMC5288169 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature