학술논문
A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation
Document Type
article
Author
Lazarian, Gregory; Yin, Shanye; Ten Hacken, Elisa; Sewastianik, Tomasz; Uduman, Mohamed; Font-Tello, Alba; Gohil, Satyen H; Li, Shuqiang; Kim, Ekaterina; Joyal, Heather; Billington, Leah; Witten, Elizabeth; Zheng, Mei; Huang, Teddy; Severgnini, Mariano; Lefebvre, Valerie; Rassenti, Laura Z; Gutierrez, Catherine; Georgopoulos, Katia; Ott, Christopher J; Wang, Lili; Kipps, Thomas J; Burger, Jan A; Livak, Kenneth J; Neuberg, Donna S; Baran-Marszak, Fanny; Cymbalista, Florence; Carrasco, Ruben D; Wu, Catherine J
Source
Cancer Cell. 39(3)
Subject
Language
Abstract
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.