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Lymphoma

Frequent mutations in the amino-terminal domain of BCL7A impair its tumor suppressor role in DLBCL

Leukemia volume 34, pages 2722–2735 (2020)Cite this article

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Abstract

Mutations in genes encoding subunits of the SWI/SNF chromatin remodeling complex are frequently found in different human cancers. While the tumor suppressor function of this complex is widely established in solid tumors, its role in hematologic malignancies is largely unknown. Recurrent point mutations in BCL7A gene, encoding a subunit of the SWI/SNF complex, have been reported in diffuse large B-cell lymphoma (DLBCL), but their functional impact remains to be elucidated. Here we show that BCL7A often undergoes biallelic inactivation, including a previously unnoticed mutational hotspot in the splice donor site of intron one. The splice site mutations render a truncated BCL7A protein, lacking a portion of the amino-terminal domain. Moreover, restoration of wild-type BCL7A expression elicits a tumor suppressor-like phenotype in vitro and in vivo. In contrast, splice site mutations block the tumor suppressor function of BCL7A by preventing its binding to the SWI/SNF complex. We also show that BCL7A restoration induces transcriptomic changes in genes involved in B-cell activation. In addition, we report that SWI/SNF complex subunits harbor mutations in more than half of patients with germinal center B-cell (GCB)-DLBCL. Overall, this work demonstrates the tumor suppressor function of BCL7A in DLBCL, and highlights that the SWI/SNF complex plays a relevant role in DLBCL pathogenesis.

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Fig. 1: Mutational patterns in BCL7A in DLBCL samples.
Fig. 2: BCL7A is targeted by AID.
Fig. 3: Loss of BCL7A_Nt domain abolishes BCL7A binding to the SWI/SNF complex.
Fig. 4: In vitro and in vivo analyses show that restoration of BCL7A drives a tumor suppressor-like phenotype.
Fig. 5: RNA-seq differential expression analyses on the OCI-LY1 and VAL cell lines after overexpression of wild-type BCL7A vs. overexpression of Δ27-BCL7A.

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Data availability

RNA-seq data discussed in this publication is accessible through Gene Expression Omnibus under accession number GSE149277. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD014795. Data will be available immediately following publication, no end date. All other data and processing code are available from the corresponding author upon reasonable request.

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Acknowledgements

PPM laboratory is supported by the Deutsche José Carreras Leukämie-Stiftung, Becas Leonardo (BBVA Foundation), the Ministry of Economy of Spain (SAF2015-67919-R), Consejería de Salud de la Junta de Andalucía (PI-0245-2017), Proyectos de I + D + I en el marco del programa operative FEDER Andalucía 2014–2020 (B-CTS-126-UGR18, PIGE-0440-2019) and, Asociación Española Contra el Cáncer (AECC). PPM laboratory would like to special acknowledge to the Heroes hasta la Médula Association and to the Aula de Investigación sobre la Leucemia infantil: Héroes contra la Leucemia. JAM-C is supported by Instituto de Salud Carlos III FIS (PI19/00818) and CIBERONC (CB16/12/00489). AA is funded by the Ministry of Science, Innovation and Universities, Spain (FPU17/00067). JCA-P is supported by a Marie Curie Fellowship (MSCA-IF-EF-RI, #837897). CB-G acknowledges the PhD program in Biochemistry and Molecular Biology, University of Granada. The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. The Genomic Variation in Diffuse Large B-Cell Lymphomas study was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. A full list of acknowledgements can be found in the Supplementary Note of the original article [25]. The results published here are in part based upon data generated by the NCI’s Clinical Trials Sequence Program and The Cancer Genome Atlas (managed by the NCI and NHGRI). The datasets have been accessed through the NIH database for Genotypes and Phenotypes (dbGaP). Information about TCGA can be found at http://cancergenome.nih.gov.

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Authors and Affiliations

  1. Gene Expression Regulation and Cancer Group (CTS-993). GENYO. Centre for Genomics and Oncological Research: Pfizer-University of Granada-Andalusian Regional Government, Granada, Spain

    Carlos Baliñas-Gavira, María I. Rodríguez, Alvaro Andrades, Marta Cuadros, Juan Carlos Álvarez-Pérez & Pedro P. Medina

  2. Department of Biochemistry and Molecular Biology I, University of Granada, Granada, Spain

    Carlos Baliñas-Gavira, María I. Rodríguez, Alvaro Andrades, Juan Carlos Álvarez-Pérez & Pedro P. Medina

  3. FIBAO - Fundación Pública para la Investigación Biosanitaria de Andalucía Oriental - Alejandro Otero, Granada, Spain

    Carlos Baliñas-Gavira

  4. Instituto de Investigación Biosanitaria de Granada (ibis.GRANADA), Granada, Spain

    María I. Rodríguez, Marta Cuadros & Pedro P. Medina

  5. Department of Biochemistry and Molecular Biology III and Immunology, University of Granada, Granada, Spain

    Marta Cuadros

  6. B Cell Biology Lab, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

    Ángel F. Álvarez-Prado, Virginia G. de Yébenes & Almudena R. Ramiro

  7. Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, 12 de Octubre Health Research Institute (imas12), Madrid, Spain

    Virginia G. de Yébenes

  8. Genomic Medicine Department, GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Granada, Spain

    Sabina Sánchez-Hernández & Francisco Martín

  9. Proteomics Unit, CNIO—Spanish National Cancer Research Center, Madrid, Spain

    Elvira Fernández-Vigo & Javier Muñoz

  10. Division of Haemato-Oncology, Centre for Applied Medical Research (CIMA), University of Navarra, CIBERONC, IDISNA, Pamplona, Spain

    José A. Martínez-Climent

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  1. Carlos Baliñas-Gavira
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Contributions

PPM conceived the study, coordinated the scientific team, and allocated the funding for the project; CB-G and MIR generated most of the experimental data; PPM and CB-G designed experiments, analyzed data, and wrote the paper; AA performed bioinformatics analyses; AA, MC, JCA-P, and JAM-C reviewed the paper; AFA-P, VGdY, and ARR designed, performed, and analyzed AID mutational study; SS-H and FM provided lentiviral vector reagents and expertize; EF-V and JM performed LC–MS/MS and proteomic data analysis; and JAM-C provided lymphoma expertise and samples. All the authors contributed with suggestions after a critical reading of the draft and approve its submission for publication.

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Correspondence to Pedro P. Medina.

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Baliñas-Gavira, C., Rodríguez, M.I., Andrades, A. et al. Frequent mutations in the amino-terminal domain of BCL7A impair its tumor suppressor role in DLBCL. Leukemia 34, 2722–2735 (2020). https://doi.org/10.1038/s41375-020-0919-5

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