A hotspot mutation p.L162R in IKZF3 drives leukemogenesis via transcriptional dysregulation

IKZF3 encodes an IKAROS Family transcription factor and has been recently identified as a novel mutated gene in chronic lymphocytic leukemia (CLL), with all mutations occurring at a single hotspot (L162R), located within the DNA binding domain of the protein. Here we show that B cell-restricted conditional knock-in of this mutation skews B cells development and induces CLL-like disease in elderly mice (30% penetrance), confirming its role as a CLL driver. Furthermore, this mutation alters the DNA binding specificity and target selection of IKZ3, leading to overexpression of BCR/NF-?B signaling genes and hyperactivation of these pathways. Likewise, we find an upregulated BCR signaling signature in human CLLs with IKZF3-L162R. Our studies highlight a novel mechanism by which a CLL driver activates the critical oncogenic BCR/NF-?B signaling axis in CLL