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Series GSE79292 Query DataSets for GSE79292
Status Public on May 25, 2016
Title Regulation of normal B cell differentiation and malignant B cell survival by OCT2 (expression)
Organisms Homo sapiens; Mus musculus
Experiment type Expression profiling by array
Summary The requirement for the B cell transcription factor OCT2 (encoded by Pou2f2) in germinal center B cells has proved controversial. Here, we report that germinal center B cells are formed normally after depletion of OCT2 in a conditional knockout mouse but that their proliferation is reduced and in vivo differentiation to antibody-secreting plasma cells is blocked. This led us to examine the role of OCT2 in germinal center derived lymphomas. ShRNA knockdown showed that almost all DLBCL cell lines are addicted to the expression of OCT2 and its co-activator OCA-B. Genome-wide chromatin Immunoprecipitation analysis and gene expression profiling revealed the broad transcriptional program regulated by OCT2 that includes the expression of STAT3, IL10, ELL2, XBP1, MYC, TERT and ADA. Importantly, genetic alteration of OCT2 is not a requirement for cellular addiction in DLBCL. However, we detected amplifications of the POU2F2 locus in DLBCL tumor biopsies as well as a recurrent mutation of threonine 223 in the DNA binding domain of OCT2. This neomorphic mutation subtly alters the DNA binding preference of OCT2 leading to the transactivation of novel target genes including HIF1a and FCRL3. Finally, by introducing mutations designed to disrupt the OCT2-OCA-B interface we reveal a requirement for this protein-protein interface that might ultimately be exploited therapeutically. Our findings, combined with the predominantly B cell restricted expression of OCT2 and the absence of systemic phenotype in our knockout mice, suggest that an OCT2-targeted therapeutic strategy would be efficacious in both major subtypes of DLBCL whilst avoiding systemic toxicity.
 
Overall design Knockdown of OCT2_1196 was tested in ABC DLBCL cell lines (HBL1 n=2, OCI-Ly10 n=3, TMD8 n=2) and GCB DLBCL cell lines (BJAB n=2, HT n=2). Knockdown of OCT2_3410 was tested in ABC DLBCL cell lines (HBL1 n=2, OCI-Ly10 n=4, TMD8 n=2) and GCB DLBCL cell lines (BJAB n=2, HT n=2). Knockdown of OCA-B was tested in ABC DLBCL cell lines (HBL1 n=2, OCI-Ly10 n=2) and GCB DLBCL cell lines (BJAB n=2, HT n=2). Knockdown of OCT2_1196 was tested with and without WT rescue construct in ABC DLBCL cell line (HBL1 n=4). Knockdown of OCT2_3410 was tested with and without WT rescue construct in ABC DLBCL cell line (HBL1 n=4). Knockdown of OCT2_1196 was tested with OCT2 T223A vs. WT rescue construct in ABC DLBCL cell line (HBL1 n=2, SUDHL4 n=4) and GCB DLBCL cell line (BJAB n=4). Mouse knockout (n=4) and wild type (n=4) Pou2f2 OCT2 B cells were tested.
 
Citation(s) 26993806
Submission date Mar 16, 2016
Last update date Mar 27, 2018
Contact name Louis M. Staudt
E-mail(s) lstaudt@mail.nih.gov
Phone 301-402-1892
Organization name National Cancer Institute
Department Lymphoid Malignancies Branch
Lab Louis M Staudt
Street address 9000 Rockville Pike, Bldg 10, Rm 4N114
City Bethesda
State/province MD
ZIP/Postal code 20892
Country USA
 
Platforms (3)
GPL4133 Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version)
GPL13912 Agilent-028005 SurePrint G3 Mouse GE 8x60K Microarray (Feature Number version)
GPL16699 Agilent-039494 SurePrint G3 Human GE v2 8x60K Microarray 039381 (Feature Number version)
Samples (57)
GSM2090955 BJAB shOCT2_1196 DOX Treated - 1 day - mAdbID:117926
GSM2090956 BJAB shOCT2_3410 DOX Treated - 1 day - mAdbID:117927
GSM2090957 BJAB shOCT2_1196 DOX Treated - 2 days - mAdbID:117928
This SubSeries is part of SuperSeries:
GSE79482 Regulation of normal B cell differentiation and malignant B cell survival by OCT2
Relations
BioProject PRJNA315886

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Supplementary file Size Download File type/resource
GSE79292_RAW.tar 976.3 Mb (http)(custom) TAR (of TXT)
Processed data included within Sample table
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