{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Lazarian G"],"funding":["NCI","NCI NIH HHS","NIH"],"pagination":["380-393.e8"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8034546"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["39(3)"],"pubmed_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."],"journal":["Cancer cell"],"pubmed_title":["A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation."],"pmcid":["PMC8034546"],"funding_grant_id":["P01 CA081534","R00 CA190861","R01 CA216273","R50 CA251956","U10 CA180861","P01 CA206978","R01 CA240910"],"pubmed_authors":["Sewastianik T","Georgopoulos K","Lazarian G","Neuberg DS","Kim E","Baran-Marszak F","Joyal H","Wang L","Billington L","Zheng M","Rassenti LZ","Livak KJ","Lefebvre V","Kipps TJ","Yin S","Uduman M","Ten Hacken E","Gohil SH","Gutierrez C","Cymbalista F","Font-Tello A","Huang T","Li S","Wu CJ","Witten E","Burger JA","Carrasco RD","Severgnini M","Ott CJ"],"additional_accession":[]},"is_claimable":false,"name":"A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation.","description":"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.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 Mar","modification":"2026-05-31T07:05:31.01Z","creation":"2025-04-05T09:49:43.684Z"},"accession":"S-EPMC8034546","cross_references":{"pubmed":["33689703"],"doi":["10.1016/j.ccell.2021.02.003"]}}