TitleSmc3 dosage regulates B cell transit through germinal centers and restricts their malignant transformation.
Publication TypeJournal Article
Year of Publication2021
AuthorsRivas, Martín A., Meydan Cem, Chin Christopher R., Challman Matt F., Kim Daleum, Bhinder Bhavneet, Kloetgen Andreas, Viny Aaron D., Teater Matt R., McNally Dylan R., Doane Ashley S., Béguelin Wendy, Fernández María Teresa Cal, Shen Hao, Wang Xiang, Levine Ross L., Chen Zhengming, Tsirigos Aristotelis, Elemento Olivier, Mason Christopher E., and Melnick Ari M.
JournalNat Immunol
Volume22
Issue2
Pagination240-253
Date Published2021 02
ISSN1529-2916
KeywordsAnimals, B-Lymphocytes, Cell Cycle Proteins, Cell Differentiation, Cell Proliferation, Cell Transformation, Neoplastic, Cells, Cultured, Chondroitin Sulfate Proteoglycans, Chromosomal Proteins, Non-Histone, Dioxygenases, DNA-Binding Proteins, Gene Deletion, Gene Dosage, Gene Expression Regulation, Neoplastic, Germinal Center, Haploinsufficiency, Histone-Lysine N-Methyltransferase, Humans, Immunity, Humoral, Lymphoma, B-Cell, Lymphoma, Large B-Cell, Diffuse, Mice, Inbred C57BL, Mice, Knockout, Myeloid-Lymphoid Leukemia Protein, Proto-Oncogene Proteins, Signal Transduction
Abstract

<p>During the germinal center (GC) reaction, B cells undergo extensive redistribution of cohesin complex and three-dimensional reorganization of their genomes. Yet, the significance of cohesin and architectural programming in the humoral immune response is unknown. Herein we report that homozygous deletion of Smc3, encoding the cohesin ATPase subunit, abrogated GC formation, while, in marked contrast, Smc3 haploinsufficiency resulted in GC hyperplasia, skewing of GC polarity and impaired plasma cell (PC) differentiation. Genome-wide chromosomal conformation and transcriptional profiling revealed defects in GC B cell terminal differentiation programs controlled by the lymphoma epigenetic tumor suppressors Tet2 and Kmt2d and failure of Smc3-haploinsufficient GC B cells to switch from B cell- to PC-defining transcription factors. Smc3 haploinsufficiency preferentially impaired the connectivity of enhancer elements controlling various lymphoma tumor suppressor genes, and, accordingly, Smc3 haploinsufficiency accelerated lymphomagenesis in mice with constitutive Bcl6 expression. Collectively, our data indicate a dose-dependent function for cohesin in humoral immunity to facilitate the B cell to PC phenotypic switch while restricting malignant transformation.</p>

DOI10.1038/s41590-020-00827-8
Alternate JournalNat Immunol
PubMed ID33432228
PubMed Central IDPMC7855695
Grant ListR01 CA228528 / CA / NCI NIH HHS / United States
R35 CA197594 / CA / NCI NIH HHS / United States
R01 AI151059 / AI / NIAID NIH HHS / United States
UL1 TR002384 / TR / NCATS NIH HHS / United States
P01 CA214274 / CA / NCI NIH HHS / United States
R01 CA249054 / CA / NCI NIH HHS / United States
R35 CA220499 / CA / NCI NIH HHS / United States
P01 CA229086 / CA / NCI NIH HHS / United States
P30 CA016087 / CA / NCI NIH HHS / United States
R01 AI125416 / AI / NIAID NIH HHS / United States
R01 CA194547 / CA / NCI NIH HHS / United States
K08 CA215317 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA216421 / CA / NCI NIH HHS / United States
R21 AI129851 / AI / NIAID NIH HHS / United States
U54 CA143869 / CA / NCI NIH HHS / United States
T32 HL135465 / HL / NHLBI NIH HHS / United States