1. A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation
- Author
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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, and Wu, Catherine J
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Hematology ,Lymphoma ,Rare Diseases ,Genetics ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,B-Lymphocytes ,Humans ,Ikaros Transcription Factor ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Mice ,Mice ,Inbred C57BL ,Mice ,Inbred NOD ,Mutation ,NF-kappa B ,Receptors ,Antigen ,B-Cell ,Signal Transduction ,Transcription ,Genetic ,BCR signaling ,CLL ,IKZF3 ,NF-κB ,murine mode ,Neurosciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - 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.
- Published
- 2021