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LYMPHOMA

Insights into the mechanisms underlying aberrant SOX11 oncogene expression in mantle cell lymphoma

Leukemia volume 36, pages 583–587 (2022)Cite this article

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Mantle cell lymphoma is characterized by the primary CCND1 deregulation caused by the t(11;14)(q13;q32) translocation. In addition, SOX11 had been described as one of the most relevant oncogenes contributing to the pathogenesis of mantle cell lymphoma (MCL) [1]. In particular, high SOX11 expression is restricted to conventional MCL (cMCL) cases, and represents a diagnostic biomarker to differentiate this MCL subtype from the less aggressive leukemic non-nodal MCL (nnMCL) and other lymphoproliferative disorders [2]. Although the consequences of SOX11 overexpression are well described [1], its causes remain widely unknown, as SOX11 is not targeted by any genetic alteration [3]. From the epigenetic perspective, the SOX11 promoter is characterized by the expected presence of activating histone modifications [4]. In 2016, we identified a distant super-enhancer 624–653 kilobases (Kb) downstream SOX11 which becomes activated and creates a three-dimensional (3D) loop structure with the SOX11 locus [5]. Here, we have performed a detailed epigenetic dissection of this distant super-enhancer to shed additional light into the mechanisms underlying SOX11 expression in cMCL.

Overall, our study dissects the SOX11 super-enhancer and identifies a small accessible region exclusively active in SOX11-positive MCL. These findings represent an additional step in the path toward understanding the causes underlying SOX11 upregulation in MCL, although further studies are required to completely elucidate the factors and chain of events associated with this oncogenic activation.

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Fig. 1: Chromosome conformation and chromatin activity at the SOX11 locus in MCL cases.
Fig. 2: Multi-omic dissection of the SOX11 super-enhancer region.

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Acknowledgements

This work was supported by research funding from the Spanish Ministerio de Ciencia, Innovación y Universidades through SAF2017-86126-R (to JIM-S), RTI2018-094274-B-I00 and PMP15/00007 which is part of Plan Nacional de I + D + I and co-financed by the ISCIII-Sub-Directorate General for Evaluation and the European Regional Development Fund (FEDER-“Una manera de Hacer Europa”) (to EC), and the National Institutes of Health, National Cancer Institute “Molecular Diagnosis, Prognosis, and Therapeutic Targets in Mantle Cell Lymphoma” (P01CA229100 to EC). Furthermore, the authors would like to thank the support of the Generalitat de Catalunya Suport Grups de Recerca AGAUR 2017-SGR-736 (to JIM-S), 2017-SGR-1142 (to EC) and 2017-SGR-468 (to MAMR), the Accelerator award CRUK/AIRC/AECC joint funder-partnership, the CERCA Programme/Generalitat de Catalunya and CIBERONC (CB16/12/00225, CB16/12/00334 and CB16/12/00489). RV-B (BES-2013-064328) was supported by a predoctoral FPI Fellowship from the Spanish Government. EC is an Academia researcher of the Catalan Institution for Research and Advanced Studies (ICREA). The authors thank the Barcelona Supercomputing Center for access to computational resources. This work was developed at the Centro Esther Koplowitz (CEK, Barcelona, Spain).

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Authors and Affiliations

  1. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Roser Vilarrasa-Blasi, Núria Verdaguer-Dot, Renée Beekman, Vicente Chapaprieta, Marta Kulis, Ana C. Queirós, Sílvia Beà, Dolors Colomer, Elías Campo & José Ignacio Martin-Subero

  2. Hospital Clínic de Barcelona and Departament de Fonaments Clínics, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain

    Roser Vilarrasa-Blasi, Sílvia Beà, Dolors Colomer, Elías Campo & José Ignacio Martin-Subero

  3. Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA

    Laura Belver & Adolfo Ferrando

  4. Josep Carreras Leukaemia Research Institute, IJC Building, Campus ICO-Germans Trias i Pujol, Barcelona, Spain

    Laura Belver & Maribel Parra

  5. CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain

    Paula Soler-Vila & Marc A. Marti-Renom

  6. Área de Oncología, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad de Navarra, Pamplona, Spain

    María José Calasanz, Xabier Agirre & Felipe Prosper

  7. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain

    María José Calasanz, Xabier Agirre, Felipe Prosper, Sílvia Beà, Dolors Colomer, Elías Campo & José Ignacio Martin-Subero

  8. Servicio de Hematología, Clínica Universidad de Navarra, Pamplona, Spain

    Felipe Prosper

  9. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

    Marc A. Marti-Renom & José Ignacio Martin-Subero

Authors
  1. Roser Vilarrasa-Blasi
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  2. Núria Verdaguer-Dot
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  18. José Ignacio Martin-Subero
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Contributions

RV-B, coordinated and performed FISH, in situ Hi–C, targeted MS, histone mark and ATAC-seq data generation and computational data analysis. NV-D, performed and supported FISH, in situ Hi–C, histone mark, and ATAC-seq data generation. LB, and AF, supported targeted MS data generation and analysis. PS-V, and MAM-R, supported in situ Hi–C computational data analysis. VC contributed in histone marks and ATAC-seq data analysis. MK, ACQ, and RB participated in DNA methylome data generation and analyses as well as in the study data interpretation. MP, MJC, XA, FP, SB, DC, EC, contributed with key reagents as well as sample collection and their biological and clinical annotation. RV-B and JIM-S directed the research and wrote the manuscript.

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Correspondence to Roser Vilarrasa-Blasi or José Ignacio Martin-Subero.

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Vilarrasa-Blasi, R., Verdaguer-Dot, N., Belver, L. et al. Insights into the mechanisms underlying aberrant SOX11 oncogene expression in mantle cell lymphoma. Leukemia 36, 583–587 (2022). https://doi.org/10.1038/s41375-021-01389-w

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