Title | Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Béguelin, Wendy, Teater Matt, Meydan Cem, Hoehn Kenneth B., Phillip Jude M., Soshnev Alexey A., Venturutti Leandro, Rivas Martín A., Calvo-Fernández María T., Gutierrez Johana, Camarillo Jeannie M., Takata Katsuyoshi, Tarte Karin, Kelleher Neil L., Steidl Christian, Mason Christopher E., Elemento Olivier, C Allis David, Kleinstein Steven H., and Melnick Ari M. |
Journal | Cancer Cell |
Volume | 37 |
Issue | 5 |
Pagination | 655-673.e11 |
Date Published | 2020 May 11 |
ISSN | 1878-3686 |
Keywords | Animals, B-Lymphocytes, Cell Transformation, Neoplastic, Cellular Reprogramming, Dendritic Cells, Enhancer of Zeste Homolog 2 Protein, Female, Germinal Center, Humans, Lymphoma, B-Cell, Lymphoma, Follicular, Mice, Mice, Inbred C57BL, Mutation |
Abstract | <p>Follicular lymphomas (FLs) are slow-growing, indolent tumors containing extensive follicular dendritic cell (FDC) networks and recurrent EZH2 gain-of-function mutations. Paradoxically, FLs originate from highly proliferative germinal center (GC) B cells with proliferation strictly dependent on interactions with T follicular helper cells. Herein, we show that EZH2 mutations initiate FL by attenuating GC B cell requirement for T cell help and driving slow expansion of GC centrocytes that become enmeshed with and dependent on FDCs. By impairing T cell help, mutant EZH2 prevents induction of proliferative MYC programs. Thus, EZH2 mutation fosters malignant transformation by epigenetically reprograming B cells to form an aberrant immunological niche that reflects characteristic features of human FLs, explaining how indolent tumors arise from GC B cells.</p> |
DOI | 10.1016/j.ccell.2020.04.004 |
Alternate Journal | Cancer Cell |
PubMed ID | 32396861 |
PubMed Central ID | PMC7298875 |
Grant List | R01 CA198089 / CA / NCI NIH HHS / United States R35 CA220499 / CA / NCI NIH HHS / United States P41 GM108569 / GM / NIGMS NIH HHS / United States R01 AI104739 / AI / NIAID NIH HHS / United States P30 CA060553 / CA / NCI NIH HHS / United States |