2. Academic Validation
  3. A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation

A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation

  • Cancer Cell. 2021 Mar 8;39(3):380-393.e8. doi: 10.1016/j.ccell.2021.02.003.
Gregory Lazarian 1,  Shanye Yin 2,  Elisa Ten Hacken 2,  Tomasz Sewastianik 3,  Mohamed Uduman 4,  Alba Font-Tello 5,  Satyen H Gohil 6,  Shuqiang Li 7,  Ekaterina Kim 8,  Heather Joyal 9,  Leah Billington 9,  Elizabeth Witten 9,  Mei Zheng 10,  Teddy Huang 11,  Mariano Severgnini 12,  Valerie Lefebvre 13,  Laura Z Rassenti 14,  Catherine Gutierrez 2,  Katia Georgopoulos 15,  Christopher J Ott 16,  Lili Wang 17,  Thomas J Kipps 18,  Jan A Burger 8,  Kenneth J Livak 19,  Donna S Neuberg 20,  Fanny Baran-Marszak 21,  Florence Cymbalista 21,  Ruben D Carrasco 22,  Catherine J Wu 23
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; INSERM, U978, Université Paris 13, Bobigny, France; Laboratoire d'Hématologie, APHP Hôpital Avicenne, Bobigny, France.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
  • 3 Harvard Medical School, Boston, MA, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
  • 4 Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Academic Haematology, University College London, London, UK.
  • 7 Broad Institute of MIT and Harvard, Cambridge, MA, USA; Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 8 Department of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 9 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 10 Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
  • 11 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 12 Center for Immuno-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • 13 Laboratoire d'Hématologie, APHP Hôpital Avicenne, Bobigny, France.
  • 14 Moores Cancer Center, University of California, San Diego, USA.
  • 15 Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
  • 16 Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 17 Department of Systems Biology, Beckman Research Institute, City of Hope National Comprehensive Cancer Center, Monrovia, CA, USA.
  • 18 Division of Hematology-Oncology, Department of Medicine, Moores Cancer Center, University of California, San Diego, USA.
  • 19 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 20 Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 21 INSERM, U978, Université Paris 13, Bobigny, France; Laboratoire d'Hématologie, APHP Hôpital Avicenne, Bobigny, France.
  • 22 Harvard Medical School, Boston, MA, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
  • 23 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: cwu@partners.org.
PMID: 33689703 DOI: 10.1016/j.ccell.2021.02.003
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.

Keywords

BCR signaling; CLL; IKZF3; NF-κB; murine mode.

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