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High resolution ChIP sequencing reveals novel bindings targets and prognostic role for SOX11 in Mantle cell lymphoma (RNA-Seq)

ABSTRACT: SOX11 (Sex determining region Y-box 11) expression is specific for MCL as compared to other Non-Hodgkin’s lymphomas. However, the function and direct binding targets of SOX11 in MCL are largely unknown. We used high-resolution ChIP-Seq to identify the direct target genes of SOX11 in a genome-wide, unbiased manner and elucidate its functional significance. Pathway analysis identified WNT, PKA and TGF-beta signaling pathways as significantly enriched by SOX11 target genes. qCHIP confirmed that SOX11 directly binds to individual genes in these pathways in both MCL cell lines and patients. Interrogation of an eighty-two patient gene-expression dataset demonstrated that SOX11 mRNA expression was inversely proportional to Ki-67, a marker of cell proliferation. Functional studies using RNA interference demonstrate that SOX11 directly regulates WNT signaling and modulates chemotherapy sensitivity to cytarabine in MCL. We analyzed SOX11 expression in three independent well-annotated tissue microarrays from the University of Wisconsin (UW), Karolina Institute and British Columbia Cancer Agency (BCCA). Our findings suggest that high SOX11 expression is associated with improved survival in a subset of MCL patients, particularly those treated with intensive chemotherapy incorporating cytarabine. Transcriptional regulation of WNT and other biological pathways affects by SOX11 target genes may help explain the impact of SOX11 expression on patient outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE52148 | GEO | 2014/08/07

SECONDARY ACCESSION(S): PRJNA227025

REPOSITORIES: GEO

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High resolution ChIP sequencing reveals novel bindings targets and prognostic role for SOX11 in Mantle cell lymphoma (RNA-Seq)

Project description:SOX11 (Sex determining region Y-box 11) expression is specific for MCL as compared to other Non-HodgkinM-bM-^@M-^Ys lymphomas. However, the function and direct binding targets of SOX11 in MCL are largely unknown. We used high-resolution ChIP-Seq to identify the direct target genes of SOX11 in a genome-wide, unbiased manner and elucidate its functional significance. Pathway analysis identified WNT, PKA and TGF-beta signaling pathways as significantly enriched by SOX11 target genes. qCHIP confirmed that SOX11 directly binds to individual genes in these pathways in both MCL cell lines and patients. Interrogation of an eighty-two patientM-BM- gene-expression dataset demonstrated that SOX11 mRNA expression was inversely proportional to Ki-67, a marker of cell proliferation. Functional studies using RNA interference demonstrate that SOX11 directly regulates WNT signaling and modulates chemotherapy sensitivity to cytarabine in MCL. We analyzed SOX11 expression in three independent well-annotated tissue microarrays from the University of Wisconsin (UW), Karolina Institute and British Columbia Cancer Agency (BCCA). Our findings suggest that high SOX11 expression is associated with improved survival in a subset of MCL patients, particularly those treated with intensive chemotherapy incorporating cytarabine. Transcriptional regulation of WNT and other biological pathways affects by SOX11 target genes may help explain the impact of SOX11 expression on patient outcomes. RNA-seq experiments studying SOX11-mediated regulation of gene transcription by examining genes differentially expressed following SOX11 depletion in 3 MCL cell lines, Granta-519, Z138 and JEKO-1

2014-08-07 | E-GEOD-52148 | biostudies-arrayexpress

High resolution ChIP sequencing reveals novel bindings targets and prognostic role for SOX11 in Mantle cell lymphoma (ChIP-Seq)

Project description:SOX11 (Sex determining region Y-box 11) expression is specific for MCL as compared to other Non-Hodgkin’s lymphomas. However, the function and direct binding targets of SOX11 in MCL are largely unknown. We used high-resolution ChIP-Seq to identify the direct target genes of SOX11 in a genome-wide, unbiased manner and elucidate its functional significance. Pathway analysis identified WNT, PKA and TGF-beta signaling pathways as significantly enriched by SOX11 target genes. qCHIP confirmed that SOX11 directly binds to individual genes in these pathways in both MCL cell lines and patients. Interrogation of an eighty-two patient gene-expression dataset demonstrated that SOX11 mRNA expression was inversely proportional to Ki-67, a marker of cell proliferation. Functional studies using RNA interference demonstrate that SOX11 directly regulates WNT signaling and modulates chemotherapy sensitivity to cytarabine in MCL. We analyzed SOX11 expression in three independent well-annotated tissue microarrays from the University of Wisconsin (UW), Karolina Institute and British Columbia Cancer Agency (BCCA). Our findings suggest that high SOX11 expression is associated with improved survival in a subset of MCL patients, particularly those treated with intensive chemotherapy incorporating cytarabine. Transcriptional regulation of WNT and other biological pathways affects by SOX11 target genes may help explain the impact of SOX11 expression on patient outcomes.

2014-08-07 | GSE52146 | GEO

SOX11 Gene Expression Profiling

Project description:The neural transcription factor SOX11 is overexpressed in aggressive lymphoid neoplasms mainly in mantle cell lymphoma (MCL), but its functional role in malignant B-cells is unknown. To identify target genes transcriptionally regulated by SOX11 in malignant lymphoid cells, we have used Gene Expression Profiling (GEP) after SOX11 silencing in MCL cell lines. Differential gene expression between Z138-shSOX11 and Z138-shControl MCL cell lines. To determine the transcriptional programs regulated by SOX11, we first generated an MCL cellular model with reduced SOX11 protein levels by infecting MCL cell lines with lentiviral particles carrying shRNA plasmids specifically targeting SOX11 (shSOX11.1 and shSOX11.3). Next, we compared the GEP of shSOX11 and shControl Z138 stable transduced clones using the Affymetrix U133+2.0 microarrays.

2013-04-04 | E-GEOD-34763 | biostudies-arrayexpress

SOX11 Gene Expression Profiling

2013-04-04 | GSE34763 | GEO

SOX11-positive and SOX11-knockdown xenograft derived tumor Gene Expression Profilings

2014-11-04 | GSE52892 | GEO

SOX11-positive and SOX11-knockdown xenograft derived tumor Gene Expression Profilings

Project description:The neural transcription factor SOX11 is overexpressed in aggressive lymphoid neoplasms mainly in mantle cell lymphoma (MCL). We have recently demonstrated SOX11 tumorigenic potential in vivo by showing a significant reduction on tumor growth of SOX11-knockdown MCL cells in xenograft experiments, confirming the clinical observations that SOX11 may play an important role in the aggressive behavior of MCL (Vegliante et al., 2013). However, the specific mechanisms regulated by SOX11 that promote the oncogenic and rapid tumor growth of aggressive MCL still remain to be elucidated. To further characterize the potential oncogenic mechanisms regulated by SOX11 in MCL, we have analyzed the GEP derived from the xenograft SOX11-positive and knockdown xenograft derived tumors. Differential gene expression between SOX11-positive Z138 and SOX11-negative Z138 MCL cell lines xenotransplanted in SCID mices derived tumors. To determine the transcriptional programs regulated by SOX11 we first generated a MCL cellular model with reduced SOX11 protein levels by infecting MCL cell lines with lentiviral particles carrying shRNA plasmids specifically targeting SOX11 (shSOX11.1 and shSOX11.3). Next, CB17-severe combined immunodeficient (CB17-SCID) mice (Charles River Laboratory, Wilmington, MA) were subcutaneously inoculated into their lower dorsum with Z138 shSOX11.1, shSOX11.3, shControl in Matrigel basement membrane matrix and compared the GEP of SOX11-positive and SOX11-negative MCL xenotransplant derived tumors using the Affymetrix U133+2.0 microarrays.

2014-11-04 | E-GEOD-52892 | biostudies-arrayexpress

Tumorigenic role of Musashi-2 in aggressive mantle cell lymphoma

Project description:SOX11 is overexpressed in the highly aggressive conventional mantle cell lymphoma (MCL) but rarely in the indolent non-nodal MCL subtype. We performed RNA-seq of SOX11+ and SOX11- MCLs to search for SOX11-regulated genes that contributed to MCL clinical evolution, identifying Musashi-2 (MSI2) stem cell-related gene. By performing RNA-seq upon MSI2 knockdown or inhibition in MCL, we identified MSI2 as a potential target to inhibit drug resistance in aggressive MCLs.

| EGAS00001006613 | EGA

The genes regulated by SOX11 in mantle cell lymphoma

Project description:The genes regulated by SOX11 in MCL was investigated in MCL cell line Granta 519 by siRNA knock down system. Cells were transfected using the LONZA electroporation system. Results represent cells harvested after 20 hours. Details of the experiment is published in PMID 21124928. Gene expression profiles (Human Gene 1.0 ST) of mantle cell lymphoma (MCL) cell line Granta 519 treated with SOX11 siRNA. Data analyses were performed using the Affymetrix Expression Console (v. 1.1)

2010-11-29 | E-GEOD-25621 | biostudies-arrayexpress

CCND2 rearrangements are the most frequent genetic events in Cyclin D1-negative mantle cell lymphoma [Agilent]

Project description:Cyclin D1-negative mantle cell lymphomas (MCL) are not well characterized, in part due to the difficulties in their recognition. SOX11 has been recently identified as a reliable biomarker of MCL, also expressed in the cyclin D1-negative variant. We investigated 40 lymphomas with MCL morphology and immunophenotype, negative for cyclin D1 expression/t(11;14)(q13;q32) but SOX11-positive. These tumors presented clinically with generalized lymphadenopathy, advanced stage, and had a poor outcome (5-year overall survival 48%). Chromosomal rearrangements of the CCND2 locus were detected in 55% of the cases, with an IG gene as partner in 18/22 cases, in particular with light chains (10 IGK@, 5 IGL@). No mutations in the phosphorylation motifs of CCND1, CCND2 and CCND3 were detected. The global genomic profile and the high complexity of the 32 cyclin D1-negative SOX11-positive MCL analyzed by copy number arrays were similar to the conventional cyclin D1/SOX11-positive MCL. 17p deletions and high Ki67 expression conferred a significantly worse outcome to the patients. This comprehensive characterization of a large series of cyclin D1-negative MCL indicates that these tumors are clinically and biologically similar to the conventional cyclin D1-positive MCL and provides a basis for the proper identification and clinical management of these patients.

2012-12-19 | GSE42917 | GEO

CCND2 rearrangements are the most frequent genetic events in Cyclin D1-negative mantle cell lymphoma [Affymetrix]

2012-12-19 | GSE42935 | GEO

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