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
  • 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: [email protected].
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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