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BTG1 mutation yields super-competitive B cells primed for malignant transformation

ABSTRACT: BTG1 mutation yields super-competitive B cells primed for malignant transformation

PROVIDER: PRJNA705197 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13796821.fastq.gz	Fastqsanger.gz
	SRR13796822.fastq.gz	Fastqsanger.gz
	SRR13796823.fastq.gz	Fastqsanger.gz
	SRR13796824.fastq.gz	Fastqsanger.gz
	SRR13796825.fastq.gz	Fastqsanger.gz

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BTG1 mutation yields super-competitive B cells primed for malignant transformation

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.

2023-01-24 | GSE167786 | GEO

<i>BTG1</i> mutation yields supercompetitive B cells primed for malignant transformation.

Project description:Multicellular life requires altruistic cooperation between cells. The adaptive immune system is a notable exception, wherein germinal center B cells compete vigorously for limiting positive selection signals. Studying primary human lymphomas and developing new mouse models, we found that mutations affecting BTG1 disrupt a critical immune gatekeeper mechanism that strictly limits B cell fitness during antibody affinity maturation. This mechanism converted germinal center B cells into supercompetitors that rapidly outstrip their normal counterparts. This effect was conferred by a small shift in MYC protein induction kinetics but resulted in aggressive invasive lymphomas, which in humans are linked to dire clinical outcomes. Our findings reveal a delicate evolutionary trade-off between natural selection of B cells to provide immunity and potentially dangerous features that recall the more competitive nature of unicellular organisms.

| S-EPMC10515739 | biostudies-literature

Loss of BTG1 function promotes ETV6-RUNX1-mediated leukemic transformation by upregulation of BCL6

Project description:Analysis of gene signatures in WT+Ctrl vs WT+ETV6-RUNX1, Btg1-/- and Btg1-/-+ETV6-RUNX1 in cKit+Ter119- fetal liver-derived hematopoietic progenitor cells (FL-HPCs). The Btg1-/-+ETV6-RUNX1 FL-HPCs display a strong increase in proliferation compared to WT+ETV6-RUNX1. Total RNA otained from WT+Ctrl, WT+ETV6-RUNX1, Btg1-/-+Ctrl and Btg1-/-+ETV6-RUNX1 FL-HPCs cells that were cultured for 12 days in expansion medium.

2014-08-22 | E-GEOD-60589 | biostudies-arrayexpress

Loss of BTG1 function promotes ETV6-RUNX1-mediated leukemic transformation by upregulation of BCL6

2014-08-22 | GSE60589 | GEO

Competitive repopulation of an empty microglial yields functionally distinct subsets of microglia-like cells

Project description:Competitive repopulation of an empty microglial yields functionally distinct subsets of microglia-like cells

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BTG1 regulates glucocorticoid receptor autoinduction in acute lymphoblastic leukemia

Project description:RNAi mediated knockdown of BTG1 in the acute lymphoblastic cell line RS4;11 causes this cell line to become resistant to prednisolone treatment when compared to control cells. In this experiment we treated BTG1 knockdown RS4;11 cells and control RS4;11 cells either with prednisolone or a vehicle control and compared the gene expression patterns of these cell lines. 8 samples were analyzed: we treated RS4;11 control or RS4;11 shRNA BTG1 cells with either prednisolone or vehicle control, the experiment was performed in duplicate. Genes with a > 2-fold change in expression after prednisolone treatment when compared to vehicle treatment were selected. Expression changes in BTG1 knockdown cells were compared to those in control vector transduced cells.

2010-06-23 | E-GEOD-18027 | biostudies-arrayexpress

BTG1 and BTG2 Regulate B Linege Commitment by Modulation of EBF1 Activity

Project description:The human BTG1 and BTG2 genes are targeted by genetic alterations in hematological malignancies. In this study we examined the unique and overlapping functions of Btg1 and Btg2 in mouse B cell development. Mice deficient for Btg1 and Btg2 displayed the strongest phenotype with a decrease in B cell numbers in bone marrow due to impaired B cell commitment and immature B cell differentiation. To determine the underlying mechanism, microarray expression analyis was performed on early (B220+ CD43+) and late (B220+ CD43-) B cells of WT and Btg1;Btg2 dKO mice.

2014-03-19 | GSE55997 | GEO

BTG1 modulates ATF4 function in response to cellular stress: implications for tumor cell survival

Project description:Analysis of the effect of glutamine starvation in mouse embryonic fibroblasts (MEFs) with and without Btg1 at gene expression level. The hypothesis tested in the present study was that loss of Btg1 affect the expression of stress-response genes. Results provide important information of the differentially expressed genes regulated by Btg1 upon glutamine deprivation, explaining the survival advantage of tumor cells harboring Btg1 loss under cellular stress condition.

2014-11-26 | GSE63642 | GEO

BTG1 regulates glucocorticoid receptor autoinduction in acute lymphoblastic leukemia

2010-06-15 | GSE18027 | GEO

BTG1 and BTG2 Regulate B Linege Commitment by Modulation of EBF1 Activity

2014-03-19 | E-GEOD-55997 | biostudies-arrayexpress