|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Lazarian, G, Yin, S, Hacken, ETen, Sewastianik, T, Uduman, M, Font-Tello, A, Gohil, SH, Li, S, Kim, E, Joyal, H, Billington, L, Witten, E, Zheng, M, Huang, T, Severgnini, M, Lefebvre, V, Rassenti, LZ, Gutierrez, C, Georgopoulos, K, Ott, CJ, Wang, L, Kipps, TJ, Burger, JA, Livak, KJ, Neuberg, DS, Baran-Marszak, F, Cymbalista, F, Carrasco, RD, Wu, CJ|
|Date Published||2021 Mar 08|
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.
|Alternate Journal||Cancer Cell|