Small-RNA expression in normal and malignant mature B cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE56354 | GEO | 2014/06/01
SECONDARY ACCESSION(S): PRJNA243025
REPOSITORIES: GEO
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Project description:Small-RNA profiles were generated for normal mature germinal center (GC) B cells and GC-derived lymphomas. Normal and tumor samples are derived from different donors.
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Project description:The MEF2B transcription factor is recurrently mutated in germinal-center (GC)-derived B-cell lymphomas, but its role in normal and neoplastic GC development is unknown. Here we identify MEF2B transcriptional targets in GC, which indicate its control of cell proliferation, apoptosis, GC confinement and differentiation. Consistently, Mef2b deletion reduces GC formation in mice. The most common tumor-associated MEF2B mutant (MEF2BD83V) is hypomorphic, but escapes binding and negative regulation by Cabin1 and HDACs. Mef2bD83V expression leads to GC enlargement and GC-derived tumors in 25% of the animals. This phenotype becomes fully penetrant in combination with BCL2 de-regulation, an event commonly associated with MEF2B mutations in human lymphoma. These results identify MEF2B as a critical GC regulator, and as a dominant oncogene in lymphomagenesis.
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Project description:miRNA profiling has been performed on normal mature B cells at different stages of differentiation (naive, germinal center and memory). The main goal is to identify miRNA signatures associated with differentiation stages of normal B cells. Keywords: miRNA, normal mature B cells
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Project description:Mutations in the BTG1 tumor suppressor gene are exclusive to germinal center (GC)-derived B cell lymphomas and associate with low clinical outcome. To elucidate the effect of BTG1 mutations in mature B cells, we generated a mouse model for the conditional expression of mutant Btg1 Unlike conventional lymphoma oncogenes, mutated Btg1 expression in B cells did not induce GC hyperplasia. However, placing mutant and wild-type GC B cells in direct competition revealed that mutant Btg1 provides a massive advantage during the GC reaction. Furthermore, mutant Btg1 accelerates and dramatically increases the aggressiveness of BCL2-driven lymphomas in vivo. NGS, cellular and molecular profiling showed activation of Myc and mTORC1 anabolic programs in Btg1 mutant GC B cells, murine lymphomas and patient DLBCLs. These programs characterize T cell-selected GC B cells that enter a growth phase prior to clonal burst. We find that mutant Btg1 sensitizes GC B cells to T cell signals, resulting in a lower threshold to Myc activation, through mRNA translational biochemical mechanisms. Together, we link recurrent mutations of BTG1 to a massive fitness gain of GC B cells that confers an agressive and invasive phenotype to B cell lymphomas in vivo and associate with low clinical outcome in patients with agressive DLBCL. This work reveals a fine-tuned metabolic regulatory network that controls normal GC development and can be hijacked by lymphoma cells during disease progression. These findings have implications for fitness processes and natural selection at a broad level by providing fundamental insight into the power of subtle biochemical shifts to enhance biological fitness of cells.
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Project description:miRNA profiling has been performed on normal mature B cells at different stages of differentiation (naive, germinal center and memory). The main goal is to identify miRNA signatures associated with differentiation stages of normal B cells. Keywords: miRNA, normal mature B cells Cells were isolated by magnetic cell sorting from tonsil tissues obtained from pediatric donors. Each phenotype is represented by 6 samples, each isolated from a different donor. The experiment does not include technical replicates.
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Project description:This study seeks to understand the mechanisms behind enhanced lymphomagenesis observed in ImHABCL6/Uchl1 mice compared with ImHABCL6 alone. As the lymphomas arise from germinal center (GC) B-cells, we reasoned that transgenic Uchl1 altered the gene expression patterns in GC B-cells from these animals. We therefore isolated pre-malignant GC B-cells and examined the gene expression patterns to identify pathways affected by the addition of Uchl1. Germinal center B-cells were isolated from from the spleens of ImHABCL6 and ImHABCL6/Uchl1 mutant mice (n= 3 each) after immunization with sheep red blood cells. RNA was extracted and hybridized to affymetrix mouse 430 2.0 arrays.
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Project description:microRNAs (miRNAs) regulate virtually all biological processes, but little is known of their role in germinal center (GC) B cells. While the GC reaction is crucial to ensure a competent immune response, GC B cells are also the origin of most human lymphomas. Here we report that miR-217 is specifically upregulated in GC B cells. Gain- and loss-of-function mouse models reveal that miR-217 functions as a positive modulator of the GC response through the regulation of a DNA repair gene network. Moreover, we show that miR-217 overexpression promotes mature B cell lymphomagenesis. Therefore miR-217 provides a novel molecular link between the normal GC response and B cell transformation
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