TBL1XR1 Mutations Drive Extranodal Lymphoma by Inducing a Pro-tumorigenic Memory Fate

Leandro Venturutti1, Matt Teater1, Andrew Zhai2, Amy Chadburn3, Leena Babiker1, Daleum Kim1, Wendy Béguelin1, Tak C Lee1, Youngjun Kim4, Christopher R Chin5, William T Yewdell6, Brian Raught7, Jude M Phillip1, Yanwen Jiang1, Louis M Staudt8, Michael R Green9, Jayanta Chaudhuri10, Olivier Elemento11, Pedro Farinha12, Andrew P Weng13, Michael D Nissen14, Christian Steidl12, Ryan D Morin12, David W Scott12, Gilbert G Privé15, Ari M Melnick16

  1. Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.
  2. Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
  3. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
  4. Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
  5. Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Tri-Institutional Program in Computational Biology and Medicine, New York, NY 10065, USA.
  6. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  7. Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 1L7, Canada.
  8. Center for Cancer Genomics, National Cancer Institute, Bethesda, MD 20892, USA.
  9. Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  10. Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA; Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Gerstner Sloan Kettering Graduate School of Biomedical Sciences, New York, NY 10065, USA.
  11. Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
  12. Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada.
  13. Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada; Department of Pathology and Lab Medicine, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada.
  14. Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC V5Z1L3, Canada.
  15. Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, and Princess Margaret Cancer Centre, Toronto, ON M5S 1A8, Canada.
  16. Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA. Electronic address: amm2014@med.cornell.edu.

Abstract

The most aggressive B cell lymphomas frequently manifest extranodal distribution and carry somatic mutations in the poorly characterized gene TBL1XR1. Here, we show that TBL1XR1 mutations skew the humoral immune response toward generating abnormal immature memory B cells (MB), while impairing plasma cell differentiation. At the molecular level, TBL1XR1 mutants co-opt SMRT/HDAC3 repressor complexes toward binding the MB cell transcription factor (TF) BACH2 at the expense of the germinal center (GC) TF BCL6, leading to pre-memory transcriptional reprogramming and cell-fate bias. Upon antigen recall, TBL1XR1 mutant MB cells fail to differentiate into plasma cells and instead preferentially reenter new GC reactions, providing evidence for a cyclic reentry lymphomagenesis mechanism. Ultimately, TBL1XR1 alterations lead to a striking extranodal immunoblastic lymphoma phenotype that mimics the human disease. Both human and murine lymphomas feature expanded MB-like cell populations, consistent with a MB-cell origin and delineating an unforeseen pathway for malignant transformation of the immune system.

Presented By Leandro Venturutti | ORCID iD

Cancer BiologyNicholas Liao2020-07 (Jul)