| First Author | Lazarian G | Year | 2021 |
| Journal | Cancer Cell | Volume | 39 |
| Issue | 3 | Pages | 380-393.e8 |
| PubMed ID | 33689703 | Mgi Jnum | J:303191 |
| Mgi Id | MGI:6511885 | Doi | 10.1016/j.ccell.2021.02.003 |
| Citation | Lazarian G, et al. (2021) A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation. Cancer Cell 39(3):380-393.e8 |
| abstractText | 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 kappaB (NF-kappaB) 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-kappaB 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. |
