title: High-resolution chromatin immunoprecipitation (ChIP) sequencing reveals novel binding targets and prognostic role for SOX11 in mantle cell lymphoma.
abstract: Sex determining region Y-box 11 (SOX11) expression is specific for mantle cell lymphoma (MCL) as compared with other non-Hodgkin's lymphomas. However, the function and direct-binding targets of SOX11 in MCL are largely unknown. We used high-resolution chromatin immunoprecipitation sequencing 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. Quantitative chromatin immunoprecipitation sequencing and promoter reporter assays confirmed that SOX11 directly binds to individual genes and modulates their transcription activities in these pathways in MCL. Functional studies using RNA interference demonstrate that SOX11 directly regulates WNT in MCL. We analyzed SOX11 expression in three independent well-annotated tissue microarrays from the University of Wisconsin (UW), Karolinska Institute and British Columbia Cancer Agency. Our findings suggest that high SOX11 expression is associated with improved survival in a subset of MCL patients, particularly those treated with intensive chemotherapy. Transcriptional regulation of WNT and other biological pathways affected by SOX11-target genes may help explain the impact of SOX11 expression on patient outcomes.
authors.affiliation: Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: P-Y
authors.identifier: 0000000311419790
authors.initials: PY
authors.lastname: Kuo
authors.affiliation: Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: V V
authors.initials: VV
authors.lastname: Leshchenko
authors.affiliation: 1] Department of Population Health, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, USA [2] Department of Genetics, Albert Einstein College of Medicine of Yeshiva  University, Bronx, NY, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Fazzari
authors.affiliation: Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Perumal
authors.affiliation: Albert Einstein Cancer Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, USA.
authors.forename: T
authors.initials: T
authors.lastname: Gellen
authors.affiliation: Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: T
authors.initials: T
authors.lastname: He
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: J
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: Department of Medicine, Center for Haematology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Baumgartner-Wennerholm
authors.affiliation: Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Nygren
authors.affiliation: Bioinformatics Laboratory, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Bioinformatics Laboratory, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Genomics and Biomarkers Program, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Suh
authors.affiliation: Genomics and Biomarkers Program, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA.
authors.forename: A
authors.initials: A
authors.lastname: Goy
authors.affiliation: Department of Pathology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
authors.forename: D T
authors.initials: DT
authors.lastname: Yang
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: W-C
authors.initials: WC
authors.lastname: Chan
authors.affiliation: Department of Medicine, School of Medicine and Public Health, and The UW Carbone Cancer Center, University of Wisconsin, Madison, WI, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Kahl
authors.affiliation: Albert Einstein Cancer Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Verma
authors.affiliation: Department of Pathology and Experimental Therapeutics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: R D
authors.initials: RD
authors.lastname: Gascoyne
authors.affiliation: Department of Medicine, Center for Haematology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Kimby
authors.affiliation: Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Sander
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, USA.
authors.forename: B H
authors.initials: BH
authors.lastname: Ye
authors.affiliation: 1] Hematology and Oncology Division, Weill Cornell Medical College, New York, NY, USA [2] Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Melnick
authors.affiliation: Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Parekh
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D001665:Binding Sites; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D059372:Nucleotide Motifs; D011379:Prognosis; D011485:Protein Binding; D055751:SOXC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C097473:SOX11 protein, human; D055751:SOXC Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin