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Nat Immunol ; 24(6): 991-1006, 2023 06.
Article in English | MEDLINE | ID: mdl-37095377

ABSTRACT

Germinal center (GC) B cells undergo proliferation at very high rates in a hypoxic microenvironment but the cellular processes driving this are incompletely understood. Here we show that the mitochondria of GC B cells are highly dynamic, with significantly upregulated transcription and translation rates associated with the activity of transcription factor A, mitochondrial (TFAM). TFAM, while also necessary for normal B cell development, is required for entry of activated GC precursor B cells into the germinal center reaction; deletion of Tfam significantly impairs GC formation, function and output. Loss of TFAM in B cells compromises the actin cytoskeleton and impairs cellular motility of GC B cells in response to chemokine signaling, leading to their spatial disorganization. We show that B cell lymphoma substantially increases mitochondrial translation and that deletion of Tfam in B cells is protective against the development of lymphoma in a c-Myc transgenic mouse model. Finally, we show that pharmacological inhibition of mitochondrial transcription and translation inhibits growth of GC-derived human lymphoma cells and induces similar defects in the actin cytoskeleton.


Subject(s)
Lymphoma, B-Cell , Lymphoma , Mice , Humans , Animals , B-Lymphocytes/pathology , Germinal Center/pathology , Transcription, Genetic , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/pathology , Mice, Transgenic , Tumor Microenvironment
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