@article{cb10069445ef430a9c4c968dec086134,
title = "A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation",
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. Lazarian et al. show that mutation in the transcription factor Ikzf3 drives CLL development in elderly mice with features reflective of human disease. In human and murine CLL, mutant IKZF3 exerts its oncogenic function by activating BCR and NF-κB signaling, is phenocopied by IKZF3 overexpression, and confers increased B cell fitness upon exposure to BCR signaling inhibitors.",
keywords = "BCR signaling, CLL, IKZF3, NF-κB, murine mode",
author = "Gregory Lazarian and Shanye Yin and {ten Hacken}, Elisa and Tomasz Sewastianik and Mohamed Uduman and Alba Font-Tello and Gohil, {Satyen H.} and Shuqiang Li and Ekaterina Kim and Heather Joyal and Leah Billington and Elizabeth Witten and Mei Zheng and Teddy Huang and Mariano Severgnini and Valerie Lefebvre and Rassenti, {Laura Z.} and Catherine Gutierrez and Katia Georgopoulos and Ott, {Christopher J.} and Lili Wang and Kipps, {Thomas J.} and Burger, {Jan A.} and Livak, {Kenneth J.} and Neuberg, {Donna S.} and Fanny Baran-Marszak and Florence Cymbalista and Carrasco, {Ruben D.} and Wu, {Catherine J.}",
note = "Funding Information: We are grateful to Drs. Paloma Cejas and Henry Long (Center for Functional Cancer Epigenetics), and Andreas Agathangelidis (Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece), for constructive and valuable discussions. We acknowledge Taghi Manshouri, BS, MS (University of Texas MD Anderson Cancer Center, Houston) for expert technical support. We acknowledge Sam Pollock, Neil Ruthen, Hayley Lyon, Oriol Olive, Lan Nguyen, Candace Patterson, and Alicia Wong for expert project management. We thank Fara Faye Regis and the Dana-Farber Cancer Institute animal research facility technical team for excellent technical support. This study was supported by a grant from the NIH/National Cancer Institute (NIH/NCI) (P01 CA206978 and P01-CA081534). C.J.W. acknowledges support from the NIH/NCI (R01 CA216273 and U10 CA180861) and is a scholar of the Leukemia and Lymphoma Society. G.L. was a Fulbright Scholar and was generously supported by the Fondation de France. S.Y. is supported by a Lauri Strauss Foundation fellowship. S.H.G. is a Kay Kendall Leukemia Fund Fellow. E.t.H. is a Special Fellow of the Leukemia and Lymphoma Society, and a Scholar of the American Society of Hematology. S.L. is supported by the NCI Research Specialist Award (R50CA251956-01). G.L. E.t.H. S.Y. and C.J.W. designed the experiments, analyzed data, and wrote the manuscript. T.S. S.L. H.J. L.B. E.W. W.Z. C.G. M.Z. S.P. and V.L. performed the experiments. S.Y. analyzed RNA-seq and ChIP-seq data; A.F.-T. performed ATAC-seq and ChIP-seq experiments. M.U. analyzed whole-genome sequencing data. F.C. F.B.-M. J.A.B. T.J.K. and L.Z.R. provided CLL patient samples and clinical annotations. S.H.G. S.L. and K.J.L. performed bulk RNA-seq and single-cell RNA-seq analysis. M.Z. T.S. and R.D.C. analyzed immunostaining. M.S. performed the Luminex experiments. E.K. performed in vitro drug studies. L.W. C.J.O. K.G. and D.S.N. helped to design and guide the research. D.S.N. supervised statistical analyses. All authors discussed and interpreted results. C.J.W. is an equity holder of Biontech, Inc. and receives research funding from Pharmacyclics. D.S.N. has been a consultant for H3 Biomedicine and received research funding from Celgene. J.A.B. reports receiving grant support and advisory board fees from Pharmacyclics, grant support, advisory board fees, and lecture fees from Gilead, advisory board fees from AstraZeneca, and lecture fees and travel support from Janssen. T.J.K. has received research funding and/or has served as an advisor to Ascerta/AstraZeneca, Celgene, Genentech/Roche, Gilead, Janssen, Loxo Oncology, Octernal Therapeutics, Pharmacyclics/AbbVie, TG Therapeutics, VelosBio, and Verastem. Cirmtuzumab was developed by T.J.K. and licensed by the University of California to Oncternal Therapeutics, Inc. which has provided stock/options to the university and T.J.K. All other authors do not have any relevant conflict of interest. Funding Information: We are grateful to Drs. Paloma Cejas and Henry Long (Center for Functional Cancer Epigenetics), and Andreas Agathangelidis (Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece), for constructive and valuable discussions. We acknowledge Taghi Manshouri, BS, MS (University of Texas MD Anderson Cancer Center, Houston) for expert technical support. We acknowledge Sam Pollock, Neil Ruthen, Hayley Lyon, Oriol Olive, Lan Nguyen, Candace Patterson, and Alicia Wong for expert project management. We thank Fara Faye Regis and the Dana-Farber Cancer Institute animal research facility technical team for excellent technical support. This study was supported by a grant from the NIH / National Cancer Institute (NIH/NCI) ( P01 CA206978 and P01-CA081534 ). C.J.W. acknowledges support from the NIH/NCI ( R01 CA216273 and U10 CA180861 ) and is a scholar of the Leukemia and Lymphoma Society. G.L. was a Fulbright Scholar and was generously supported by the Fondation de France . S.Y. is supported by a Lauri Strauss Foundation fellowship. S.H.G. is a Kay Kendall Leukemia Fund Fellow. E.t.H. is a Special Fellow of the Leukemia and Lymphoma Society, and a Scholar of the American Society of Hematology. S.L. is supported by the NCI Research Specialist Award ( R50CA251956-01 ). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = mar,
day = "8",
doi = "10.1016/j.ccell.2021.02.003",
language = "English (US)",
volume = "39",
pages = "380--393.e8",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "3",
}
