Unravelling the recombinome of IKZF1 deletions in B-ALL

IKZF1 deletions (ΔIKZF1) are associated with an increased risk of relapse in B-ALL patients. Although a multiplex PCR (M-PCR) has been designed for the detection of recurrent ΔIKZF1 (Δ2-3, Δ2-7, Δ2-8, Δ4-7, Δ4-8), we still lack information regarding the breakpoints of non-recurrent ΔIKZF1 to provide an accurate diagnosis. Thus, we explored sequence features in pediatric and adult B-ALL patient with ∆IKZF1, and evaluated CNAs within IKZF1 locus by using MLPA. Non-recurrent ΔIKZF1 were then sequenced by targeted NGS. We also compiled DNA-seq data from literature, and mapped the breakpoint sequences for the identification of clusters and motifs associated with breakpoints. A total of 1,474 B-ALL samples were included of which 16% had ΔIKZF1. We compiled 935 breakpoint sequences of ΔIKZF1, and 24 clusters were identified. Non-recurrent ΔIKZF1 had three exclusive clusters. Heptamer-like sequences for RAG recombination were identified near those clusters, also in rare ΔIKZF1. Therefore, we provide the basis for updating M-PCR and MLPA design to facilitate the detection of almost all ΔIKZF1, and show that illegitimate RAG activity could potentially promote rare types of ΔIKZF1.

Publication History

Article published online:
17 May 2022