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

Cancer Cell. 2021 Mar 8;39(3):380-393.e8. doi: 10.1016/j.ccell.2021.02.003.


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.

Keywords: BCR signaling; CLL; IKZF3; NF-κB; murine mode.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / pathology*
  • Humans
  • Ikaros Transcription Factor / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mutation / genetics*
  • NF-kappa B / genetics
  • Receptors, Antigen, B-Cell / genetics
  • Signal Transduction / genetics
  • Transcription, Genetic / genetics*


  • IKZF3 protein, human
  • NF-kappa B
  • Receptors, Antigen, B-Cell
  • Ikaros Transcription Factor