IKZF1 Deletions with COBL Breakpoints Are Not Driven by RAG-Mediated Recombination Events in Acute Lymphoblastic Leukemia

Abstract IKZF1 deletion (Δ IKZF1 ) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-ALL with COBL rearrangements ( COBL -r). Patients with B-ALL and IKZF1 deletion ( n  = 133) were included. IKZF1 ∆1-8 were associated with large alterations within chromosome 7: monosomy 7 (18%), isochromosome 7q (10%), 7p loss (19%), and interstitial deletions (53%). The latter included COBL -r, which were found in 12% of the IKZF1 ∆1-8 cohort. Patients with COBL -r are mostly classified as intermediate cytogenetic risk and frequently harbor ETV6 , PAX5 , CDKN2A/B deletions. Overall, 56% of breakpoints were located within COBL intron 5. Cryptic recombination signal sequence motifs were broadly distributed within the sequence of COBL , and no enrichment for the breakpoint cluster region was found. In summary, a diverse spectrum of alterations characterizes Δ IKZF1 and they also include deletion breakpoints within COBL . We confirmed that COBL is a hotspot associated with Δ IKZF1 , but these rearrangements are not driven by RAG-mediated recombination.