@article{10caf70b13864d639539fc91b7c2267d,
title = "TBL1XR1 Mutations Drive Extranodal Lymphoma by Inducing a Pro-tumorigenic Memory Fate",
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.",
keywords = "ABC-DLBCL, BACH2, BCL6, TBL1XR1, cell fate, cell of origin, extranodal lymphoma, germinal center, memory B cells",
author = "Leandro Venturutti and Matt Teater and Andrew Zhai and Amy Chadburn and Leena Babiker and Daleum Kim and Wendy B{\'e}guelin and Lee, {Tak C.} and Youngjun Kim and Chin, {Christopher R.} and Yewdell, {William T.} and Brian Raught and Phillip, {Jude M.} and Yanwen Jiang and Staudt, {Louis M.} and Green, {Michael R.} and Jayanta Chaudhuri and Olivier Elemento and Pedro Farinha and Weng, {Andrew P.} and Nissen, {Michael D.} and Christian Steidl and Morin, {Ryan D.} and Scott, {David W.} and Priv{\'e}, {Gilbert G.} and Melnick, {Ari M.}",
note = "Funding Information: We thank all members of the Melnick Lab for thoughtful discussions and suggestions, and Hao Shen for his support with mice colonies. We acknowledge the Epigenomics, Genomics, and Flow Cytometry cores (WCM); the Molecular Cytology core (MSKCC); and the Center of Comparative Medicine and Pathology (WCM/MSKCC). L.V. is a Career Development Program Fellow from the Leukemia and Lymphoma Society ( 5469-18 ). A.M.M. is supported by the National Cancer Institute ( NCI -R35-CA220499) , the Leukemia and Lymphoma Society ( LLS-TRP-6572-19 , LLS-SCOR-7012-16) , the Chemotherapy Foundation , and the Follicular Lymphoma Consortium . Funding Information: We thank all members of the Melnick Lab for thoughtful discussions and suggestions, and Hao Shen for his support with mice colonies. We acknowledge the Epigenomics, Genomics, and Flow Cytometry cores (WCM); the Molecular Cytology core (MSKCC); and the Center of Comparative Medicine and Pathology (WCM/MSKCC). L.V. is a Career Development Program Fellow from the Leukemia and Lymphoma Society (5469-18). A.M.M. is supported by the National Cancer Institute (NCI-R35-CA220499), the Leukemia and Lymphoma Society (LLS-TRP-6572-19, LLS-SCOR-7012-16), the Chemotherapy Foundation, and the Follicular Lymphoma Consortium. Conceptualization, L.V. and A.M.M.; Methodology, L.V. A.M.M. W.B. and Y.J.; Formal Analysis, L.V. M.T. A.Z. A.C. C.R.C. P.F. A.P.W. Y.K. O.E. and G.G.P.; Investigation, L.V. A.Z. D.K. J.M.P. L.B. T.C.L. W.B. Y.K. W.T.Y. M.D.N. and B.R.; Resources, L.M.S. J.C. C.S. D.W.S. R.D.M. and M.R.G.; Writing, L.V. and A.M.M. A.M.M. receives research funding for Janssen, is on the scientific board of KDAC Pharmaceuticals, and has consulted for Constellation and Epizyme. M.R.G. consults for Verastem Oncology. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = jul,
day = "23",
doi = "10.1016/j.cell.2020.05.049",
language = "English (US)",
volume = "182",
pages = "297--316.e27",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "2",
}