Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response

Béguelin, W., Teater, M., Meydan, C., Hoehn, K. B., Phillip, J. M., Soshnev, A. A., Venturutti, L., Rivas, M. A., Calvo-Fernández, M. T., Gutierrez, J., Camarillo, J. M., Takata, K., Tarte, K., Kelleher, N. L., Steidl, C., Mason, C. E., Elemento, O., Allis, C. D., Kleinstein, S. H., & Melnick, A. M. (2020). Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response. Cancer cell, 37(5), 655–673.e11. https://doi.org/10.1016/j.ccell.2020.04.004

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.

Journal: Cancer Cell PMID: 32396861 DOI: 10.1016/j.ccell.2020.04.004