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Illegitimate RAG‐mediated recombination events are involved in IKZF1 Δ3–6 deletion in BCR‐ABL1 lymphoblastic leukaemia

Breakpoint cluster region‐Abelson murine leukaemia viral oncogene homologue 1 (BCR–ABL1), encoded by the Philadelphia (Ph) chromosome, is the characteristic of chronic myeloid leukaemia (CML) and a subset of acute lymphoblastic leukaemia (ALL). We demonstrated that expression of the Ik6 transcript, which lacked exons 3–6, was observed exclusively in BCR–ABL1+B ALL and lymphoid blast crisis CML (BC–CML) patients harbouring the IKZF1 Δ3–6 deletion. To confirm the hypothesis that illegitimate recombination activating gene protein (RAG)‐mediated recombination events are involved in IKZF1 Δ3–6 deletion in BCR–ABL1 lymphoblastic leukaemia, we first demonstrated that the expression rates of RAG1 and RAG2, collectively called RAG, were higher in ALL and BC–CML (lymphoid). Notably, analysis of relationships among RAG, BCR–ABL1 and Ikaros 6 (Ik6) showed that Ik6 can be generated only if RAG and BCR–ABL1 are co‐existing. The sequencing data showed that the deleted segments of introns 2 and 6 contained cryptic recombination signal sequences (cRSSs) and frequently had non‐template nucleotides inserted between breakpoints. Furthermore, we used chromatin immunoprecipitation (ChIP) technology and demonstrated that the sequences directly flanking IKZF1 Δ3–6 deletion breakpoints have significantly higher levels of histone H3 lysine 4 trimethylation (H3K4me3) modifications. Overall, RAG expression, good‐quality cRSS and a specific chromatin modification, H3K4me3, satisfy the conditions of RAG's off‐target effects on IKZF1. Our work provides evidence for RAG‐mediated IKZF1 Δ3–6 deletion. Our results raise the prospect that RAG is a valuable biomarker in disease surveillance. Dissecting the contribution of RAG should not only provide valuable mechanistic insights, but will also lead to a new therapeutic direction.