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Gene expression profiling of five diffuse large B-cell lymphoma (DLBCL) cell lines, DHL4, DHL6, LY7, HBL1 and U2932, treated with the SYK inhibitor, R406

ABSTRACT: The five DLBCL cell lines were treated with R406 to assess the signature of SYK inhibition. In previous studies, R406 decreased the proliferation and induced apoptosis of these surface Ig+ cell lines. In the previous studies, R406 inhibited the autophosphorylation of SYK 525/526 and SYK-dependent phosphorylation of BCR signaling components such as BLNK. RNA samples from five DLBCL cell lines treated with R406 or vehicle (DMSO) alone for 0, 6, or 24 hours were profiled in triplicate on Affymetrix HT_HG-U133plust2 chips.

ORGANISM(S): Homo sapiens

SUBMITTER: Stefano Monti

PROVIDER: E-GEOD-43510 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Gene expression profiling of two diffuse large B-cell lymphoma (DLBCL) cell lines, DHL4 and DHL6, treated with the SYK inhibitor, R406

Project description:The two DLBCL cell lines were treated with R406 to assess the signature of SYK inhibition. In previous studies, R406 decreased the proliferation and induced apoptosis of these surface Ig+ cell lines. In the previous studies, R406 inhibited the autophosphorylation of SYK 525/526 and SYK-dependent phosphorylation of BCR signaling components such as BLNK. RNA samples from two DLBCL cell lines, DHL4 and DHL6, treated with R406 or vehicle (DMSO) alone for 0, 2, 6, 24 or 48 hours were profiled in triplicate on Affymetrix HT_HG-U133A chips.

2013-12-31 | E-GEOD-34176 | biostudies-arrayexpress

Gene expression profiling of five diffuse large B-cell lymphoma (DLBCL) cell lines, DHL4, DHL6, LY7, HBL1 and U2932, treated with the SYK inhibitor, R406

Project description:The five DLBCL cell lines were treated with R406 to assess the signature of SYK inhibition. In previous studies, R406 decreased the proliferation and induced apoptosis of these surface Ig+ cell lines. In the previous studies, R406 inhibited the autophosphorylation of SYK 525/526 and SYK-dependent phosphorylation of BCR signaling components such as BLNK.

2013-08-31 | GSE43510 | GEO

Gene expression profiling of two diffuse large B-cell lymphoma (DLBCL) cell lines, DHL4 and DHL6, treated with the SYK inhibitor, R406

2013-12-31 | GSE34176 | GEO

Time course gene expression profiling of five diffuse large B-cell lymphoma cell lines following JQ1 treatment

Project description:To understand the molecular curcuits perturbed by BET bromodoman inhibtion we obtained gene expression profiling of five DLBCL cell lines, SU-DHL6, OCI-Ly1, OCI-Ly4, Toledo and HBL-1, which were treated with either 500nM JQ1 or DMSO for 0,2,6,12,24 and 48hr. RNA samples from five DLBCL cell lines at baseline (time 0) or following treatment with 500nM of JQ1 or vehicle (DMSO) alone for 2, 6, 24 or 48 hours were profiled in triplicate on Affymetrix Human Gene 1.0 ST Array.

2013-12-10 | E-GEOD-45630 | biostudies-arrayexpress

Whole transcriptome profiling of the two major subtypes of diffuse large B cell lymphoma

Project description:The goal of this study is to identify the transcriptome differences between the two major subtypes of diffuse large B cell lymphoma (DLBCL). DLBCL is the most common form of non-Hodgkin’s lymphoma and has two major subtypes: germinal center B-cell-like (GCB) and activated B-cell-like (ABC). When compared to the GCB form, ABC lymphomas respond much more poorly to current therapies. To investigate how gene expression changes might contribute to this aggressive phenotype, we have used RNA-Seq to profile the whole transcriptome in 8 DLBCL cell lines (4 GCB subtype, 4 ABC) that are derived from patient tumors. 1,545 genes are differentially expressed between subtypes (FDR < 0.05), approximately 7% of the transcriptome. The vast majority of these genes (81%, n = 1251) are more highly expressed in the ABC cell lines. In contrast, only 294 genes (19%) are more highly expressed in the GCB cell lines. Half (n = 765) of the genes with greater ABC subtype expression demonstrate very low read counts (< 5) in the GCB cell types. Conversely, only 21 genes that are more highly expressed in GCB are unique to that subtype. The prevalence of such “on/off” genes indicates that the major differences between ABC and GCB DLBCL are due almost exclusively to additional gene expression in ABC, rather than the two subtypes having divergent but equally active genetic programs. Measurement and comparison of gene expression in 8 cell lines representing the 2 subtypes of DLBCL. 4 cell lines are subtyped as ABC and 4 are subtyped as GCB. 2 replicates are present for each cell line. (Cell line OCI-Ly19 was not included in the analysis because its gene expression clustered in between the subtypes, probably due to its EBV+ status. However, its sequencing runs have been included for completeness.)

2013-12-16 | E-GEOD-50721 | biostudies-arrayexpress

Whole genome mapping of STAT3 binding sites in the two major subtypes of diffuse large B cell lymphoma

Project description:The goal of this study is to identify the effect of the transcription factor STAT3 in the two major subtypes of diffuse large B cell lymphoma (DLBCL). STAT3 is a signal transducer that, when dysregulated, becomes a powerful oncogene found in many human cancers, including DLBCL. DLBCL is the most common form of non-Hodgkin’s lymphoma and has two major subtypes: germinal center B-cell-like (GCB) and activated B-cell-like (ABC). When compared to the GCB form, ABC lymphomas respond much more poorly to current therapies and often exhibit overexpression or overactivation of STAT3. To investigate how STAT3 might contribute to this aggressive phenotype, we have used ChIP-Seq to identify STAT3 binding sites in 8 DLBCL cell lines (4 GCB subtype, 4 ABC) that are derived from patient tumors. 10,337 distinct STAT3 binding regions are occupied in at least two of the eight cell lines. One third (n = 3524) are differentially bound by STAT3 between the two subtypes (FDR < 0.05). More BRs are strongly bound in ABC than in GCB: 44% of differentially bound BRs (n = 1550) show more STAT3 binding in GCB, while 56% (n = 1974) are more strongly bound in ABC. Identification and comparison of STAT3 transcription factor binding sites in 8 cell lines that represent the 2 subtypes of DLBCL. 4 cell lines are subtyped as ABC and 4 are subtyped as GCB. 2-9 replicates and 1 input control are present for each cell line. (Cell line OCI-Ly19 was not included in the final analysis because RNA-Seq showed that its gene expression clustered in between the subtypes, probably due to its EBV+ status. However, its peak calls were used in intermediate steps of the analysis pipeline. Its sequencing runs have been included for completeness.)

2013-12-16 | E-GEOD-50723 | biostudies-arrayexpress

In Vivo RNA Interference Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

Project description:We used an in vivo short hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo, and for human leukemia cells in xenotransplantation studies.M-BM- In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase, Syk.M-BM- In contrast, loss of Itgb3 in normal HSPCs did not affect engraftment, reconstitution, or differentiation. M-BM- Finally, we confirmed that Itgb3 is dispensable for normal hematopoiesis and required for leukemogenesis using an Itgb3 knockout mouse model.M-BM- Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML. R940406 (R406, the active metabolite of fostamatinib) was supplied by Rigel Pharmaceuticals, Inc., South San Francisco, CA, and AstraZeneca Pharmaceuticals, Wilmington, DE, USA. R406 was resuspended in dimethyl sulfoxide (DMSO) (Sigma-Aldrich) and stored at M-bM-^HM-^R80M-BM-0C. . HL-60, U937 and KG-1 cell lines were purchased from the American Type Culture Collection. MOLM-14 cell lines were provided by Dr. Scott Amstrong (Dana-Farber Cancer Institute, Boston MA, USA.) All cell lines were maintained in RPMI 1640 (Cellgro) supplemented with 1% penicillin-streptomycin and 10% fetal bovine serum (FBS, Sigma-Aldrich) at 37 M-BM-0C with 5% CO2. MOLM-14, U937, HL-60 and KG-1 cells were grown in 4mM R406 for 24 hours

2013-04-24 | E-GEOD-46302 | biostudies-arrayexpress

DUSP4 deficiency due to promoter hypermethylation drives oncogenic JNK signaling and tumor cell survival in diffuse large B-cell lymphoma

Project description:The epigenetic dysregulation of tumor suppressor genes is a major driver of human carcinogenesis. We have combined genome-wide methylation analyses with functional screening to identify novel candidate tumor suppressor genes in diffuse large B-cell lymphoma (DLBCL). We find that the dual-specificity phosphatase DUSP4 is aberrantly silenced in nodal and extranodal DLBCL due to promoter hypermethylation; ectopic expression of wild type DUSP4, but not of a phosphatase-deficient mutant, dephosphorylates c-JUN N-terminal kinase (JNK) and induces apoptosis in DLBCL cells. JNK inhibition prevents DLBCL survival in vitro and in vivo, and synergizes strongly with inhibitors of chronic active B-cell receptor signaling. Our results provide a mechanistic basis for the clinical development of JNK inhibitors in DLBCL, alone or in synthetic lethal combinations. A methylation profiling data set related to this experiment was also deposited at ArrayExpress under accession number E-MTAB-2926: http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-2926/

2015-03-25 | E-MTAB-2925 | biostudies-arrayexpress

DUSP4 deficiency due to promoter hypermethylation drives oncogenic JNK signaling and tumor cell survival in diffuse large B-cell lymphoma (methylation profiling data)

Project description:The epigenetic dysregulation of tumor suppressor genes is a major driver of human carcinogenesis. We have combined genome-wide methylation analyses with functional screening to identify novel candidate tumor suppressor genes in diffuse large B-cell lymphoma (DLBCL). We find that the dual-specificity phosphatase DUSP4 is aberrantly silenced in nodal and extranodal DLBCL due to promoter hypermethylation; ectopic expression of wild type DUSP4, but not of a phosphatase-deficient mutant, dephosphorylates c-JUN N-terminal kinase (JNK) and induces apoptosis in DLBCL cells. JNK inhibition prevents DLBCL survival in vitro and in vivo, and synergizes strongly with inhibitors of chronic active B-cell receptor signaling. Our results provide a mechanistic basis for the clinical development of JNK inhibitors in DLBCL, alone or in synthetic lethal combinations. RNA-seq expression profiling data set related to this experiment was also deposited at ArrayExpress under accession number E-MTAB-2925: http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-2925/

2015-03-25 | E-MTAB-2926 | biostudies-arrayexpress

R406-Inhibition of Syk-Cn-NFAT Signaling Axis Promotes Chemical Reprogramming via Metabolic Rewiring and H2S Production

Project description:Small molecules not only are convenient and useful for controlling cell fates, but also can provide better understanding of the molecular mechanisms of cell-fate transitions. Here, we identified that spleen tyrosine kinase (Syk) inhibitor R406 could significantly promote the early stage of mouse chemical reprogramming. Furthermore, R406 alleviated the Syk-calcineurin (Cn)-nuclear factor of activated T cells (NFAT) signaling cascade-mediated suppression of glycine, serine and threonine metabolic genes transcriptionally, which is previously unrecognized. In turn, R406 upregulated metabolites of glycine, serine and threonine metabolism and downstream transsulfuration cysteine biosynthesis pathway and cysteine metabolism. Subsequently, increased cellular hydrogen sulfide (H2S) after R406 treatment downregulated oxidative phosphorylation (OXPHOS) and reactive oxygen species (ROS), modulated redox homeostasis, and significantly enhanced chemical reprogramming. In sum, our studies have not only improved the chemical reprogramming technique, but also identified interesting molecular mechanisms of chemical-induced pluripotent reprogramming, which hold great potentials in regenerative medicine.

2021-03-14 | GSE154687 | GEO

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