TitleTBL1XR1 Mutations Drive Extranodal Lymphoma by Inducing a Pro-tumorigenic Memory Fate.
Publication TypeJournal Article
Year of Publication2020
AuthorsVenturutti, Leandro, Teater Matt, Zhai Andrew, Chadburn Amy, Babiker Leena, Kim Daleum, B├ęguelin Wendy, Lee Tak C., Kim Youngjun, Chin Christopher R., Yewdell William T., Raught Brian, Phillip Jude M., Jiang Yanwen, Staudt Louis M., Green Michael R., Chaudhuri Jayanta, Elemento Olivier, Farinha Pedro, Weng Andrew P., Nissen Michael D., Steidl Christian, Morin Ryan D., Scott David W., Prive Gilbert G., and Melnick Ari M.
JournalCell
Volume182
Issue2
Pagination297-316.e27
Date Published2020 07 23
ISSN1097-4172
KeywordsAnimals, Basic-Leucine Zipper Transcription Factors, Chromatin, Germinal Center, Histone Deacetylases, Humans, Immunologic Memory, Lymphoma, Large B-Cell, Diffuse, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutagenesis, Site-Directed, Nuclear Proteins, Nuclear Receptor Co-Repressor 2, Precursor Cells, B-Lymphoid, Protein Binding, Proto-Oncogene Proteins c-bcl-6, Receptors, Cytoplasmic and Nuclear, Repressor Proteins, RNA Interference, RNA, Small Interfering, Transcription, Genetic
Abstract

<p>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.</p>

DOI10.1016/j.cell.2020.05.049
Alternate JournalCell
PubMed ID32619424
PubMed Central IDPMC7384961
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
P30 CA016672 / CA / NCI NIH HHS / United States
R35 CA220499 / CA / NCI NIH HHS / United States