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Series GSE167786 Query DataSets for GSE167786
Status Public on Jan 24, 2023
Title BTG1 mutation yields super-competitive B cells primed for malignant transformation
Organisms Homo sapiens; Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 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.
 
Overall design RNAseq, RIPseq
scRNAseq: BD Rhapsody Single Cell RNA sequencing in competing Btg1 Q36H and CREneg Germinal Center B cells
 
Contributor(s) Mlynarczyk C, Teater M, Chin CR, Melnick AM
Citation(s) 36656933
Submission date Feb 26, 2021
Last update date Jan 28, 2023
Contact name Matt Teater
E-mail(s) mrt2001@med.cornell.edu
Organization name Weill Cornell Medical College
Street address 445 E 69th St
City New York
State/province NY
ZIP/Postal code 10021
Country USA
 
Platforms (4)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (62)
GSM5112424 SUDHL4_BTG1wt, repl1
GSM5112425 SUDHL4_BTG1wt, repl2
GSM5112426 SUDHL4_BTG1wt, repl3
Relations
BioProject PRJNA705197
SRA SRP308405

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE167786_RAW.tar 27.4 Mb (http)(custom) TAR (of CSV, RDS, TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file
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