A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation

Hotspot mutation of IKZF3 (IKZF3-L162R) has been identified as a putative driver of chronic lymphocytic leukemia (CLL), but its function remains unknown. Here, we demonstrate its driving role in CLL through a B cell-restricted conditional knockin mouse model. Mutant Ikzf3 alters DNA binding specificity and target selection, leading to hyperactivation of B cell receptor (BCR) signaling, overexpression of nuclear factor κB (NF-κB) target genes, and development of CLL-like disease in elderly mice with a penetrance of ~40%. Human CLL carrying either IKZF3 mutation or high IKZF3 expression was associated with overexpression of BCR/NF-κB pathway members and reduced sensitivity to BCR signaling inhibition by ibrutinib. Our results thus highlight IKZF3 oncogenic function in CLL via transcriptional dysregulation and demonstrate that this pro-survival function can be achieved by either somatic mutation or overexpression of this CLL driver. This emphasizes the need for combinatorial approaches to overcome IKZF3-mediated BCR inhibitor resistance. Lazarian et al. show that mutation in the transcription factor Ikzf3 drives CLL development in elderly mice with features reflective of human disease. In human and murine CLL, mutant IKZF3 exerts its oncogenic function by activating BCR and NF-κB signaling, is phenocopied by IKZF3 overexpression, and confers increased B cell fitness upon exposure to BCR signaling inhibitors.