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.
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We thank the Epigenomics cores at Weil Cornell Medical College and Albert Einstein College of Medicine for the service support in next generation sequencing. We would also like to thank Eugenia (Jenny) Giannopoulou, PhD, and Olivier Elemento, PhD, for the assistance in ChIP-seq analysis and Chris Benner, PhD, for the support in motif analysis. We are grateful for Stuart A Aaronson, MD, for the expert consultation on WNT signaling pathway and the DN-TCF4 construct and Thomas J Kelly, MD, PhD for the SMAD3 reporter construct. This project was funded in part by the Chemotherapy Foundation (SP), Gabrielle's Angel Foundation (SP), Leukemia and Lymphoma Society Translational Research Project Grant (SP), Paul Calabresi Career Development Award K12-CA132783-01 (SP), the Swedish Cancer Society (BS), the Swedish Research Council (BS), the Cancer Society in Stockholm (BS), the Karolinska Institutet Funds (BS) and the Stockholm County Council (BS). DTY is supported by the Clinical and Translational Science Award (CTSA) program, previously through the National Center for Research Resources grant 1UL1RR025011, and now by the National Center for Advancing Translational Sciences (NCATS), grant 9U54TR000021 (DTY), grant P30 CA014520 from the National Cancer Institute and Forward Lymphoma (DTY).
The authors declare no conflict of interest.
This study was presented in part (publication number: 895) at the 54th Annual Meeting of the American Society of Hematology, Atlanta, VA, USA on 11 December 2012.
Supplementary Information accompanies this paper on the Oncogene website
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Kuo, PY., Leshchenko, V., Fazzari, M. et al. High-resolution chromatin immunoprecipitation (ChIP) sequencing reveals novel binding targets and prognostic role for SOX11 in mantle cell lymphoma. Oncogene 34, 1231–1240 (2015). https://doi.org/10.1038/onc.2014.44
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