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Bptf determines oncogenic addiction in aggressive B-cell lymphomas

Oncogene volume 39, pages 4884–4895 (2020)Cite this article

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Abstract

Chromatin remodeling factors contribute to establish aberrant gene expression programs in cancer cells and therefore represent valuable targets for therapeutic intervention. BPTF (Bromodomain PhD Transcription Factor), a core subunit of the nucleosome remodeling factor (NURF), modulates c-MYC oncogenic activity in pancreatic cancer. Here, we analyze the role of BPTF in c-MYC-driven B-cell lymphomagenesis using the Eμ-Myc transgenic mouse model of aggressive B-cell lymphoma. We find that BPTF is required for normal B-cell differentiation without evidence of haploinsufficiency. In contrast, deletion of one Bptf allele is sufficient to delay lymphomagenesis in Eμ-Myc mice. Tumors arising in a Bptf heterozygous background display decreased c-MYC levels and pathway activity, together with increased activation of the NF-κB pathway, a molecular signature characteristic of human diffuse large B-cell lymphoma (DLBCL). In human B-cell lymphoma samples, we find a strong correlation between BPTF and c-MYC mRNA and protein levels, together with an anti-correlation between BPTF and NF-κB pathway activity. Our results indicate that BPTF is a relevant therapeutic target in B-cell lymphomas and that, upon its inhibition, cells acquire distinct oncogenic dependencies.

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Fig. 1: Deletion of one Bptf allele delays lymphoma development and progression in Eμ-Myc mice.
Fig. 2: Deletion of one Bptf allele does not impair proliferation, survival, or homing of pre-leukemic BM cells.
Fig. 3: Deletion of one Bptf allele favors the development of lymphomas with low c-MYC and E2F, but high NF-κB, activation signatures.
Fig. 4: BPTF levels show a positive correlation with c-MYC and E2F, and a negative correlation with NF-κB, pathway activity in human lymphomas.

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Acknowledgements

We thank the CNIO Core facilities and ECG members for support, V. J. Sánchez-Arévalo for valuable discussions, E. Carrillo-de-Santa Pau for discussion on bioinformatics analyses, and V. de Yébenes for critical comments to a previous version of the manuscript. We thank M. Reth and C. Blanco for providing Mb1-Cre and Eμ-Myc mice, respectively. FXR was supported, in part, by grants SAF2011-29530, SAF2015-70553-R, RTI2018-101071-B-I00, and RTI2018-101071-B-I00 (Ministerio de Ciencia, Innovación y Universidades, Madrid, Spain) (co-funded by the ERDF-EU) and RTICC (RD12/0036/0034, RD12/0036/0050, Instituto de Salud Carlos III). AR was supported by ERC StG BCLYM-207844, SAF2013-42767-R, and SAF2016-75511-R grants and co-funding by Fondo Europeo de Desarrollo Regional (FEDER). CNIO is supported by Ministerio de Ciencia, Innovación y Universidades as a Centro de Excelencia Severo Ochoa SEV-2015-0510. The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Personal grants: PD and JP, Asociación Española Contra el Cáncer; IF, Amigos del CNIO/Juegaterapia; MPA, Ministerio de Ciencia, Innovación y Universidades, Spain. FXR acknowledges the support of Asociación Española Contra el Cáncer.

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Author notes

  1. These authors contributed equally: Irene Felipe, Pilar Delgado

Authors and Affiliations

  1. Epithelial Carcinogenesis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre-CNIO, 28029, Madrid, Spain

    Laia Richart, Irene Felipe, Mónica P. de Andrés, Jaime Prieto, Natalia del Pozo & Francisco X. Real

  2. B Lymphocyte Biology Lab, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029, Madrid, Spain

    Pilar Delgado & Almudena Ramiro

  3. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029, Madrid, Spain

    Natalia del Pozo, Miguel A. Piris & Francisco X. Real

  4. Department of Pathology, MD Anderson Cancer Center, 28033, Madrid, Spain

    Juan F. García

  5. Department of Pathology, Fundación Jiménez Díaz, 28040, Madrid, Spain

    Miguel A. Piris

  6. Department of Pathology, Hospital Universitario Marqués de Valdecilla, 39008, Santander, Spain

    Miguel A. Piris

  7. Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003, Barcelona, Spain

    Francisco X. Real

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Contributions

LR designed and performed the in vivo studies; processed, and analysed the RNA-sequencing data, and analysed the public expression datasets of human aggressive B-cell lymphomas. IF performed the immunohistochemical analysis of tumor samples and the western blot characterization of tumor samples. PD designed, performed, and analysed the BM transplantation experiments. MPA and JP contributed to the conduct of the experimental work. NP provided technical support with mouse colony maintenance. JFG contributed to the histopathological analysis of mouse lymphomas. MAP provided human samples for histological evaluation. AR contributed to experimental design, provided scientific insight, and contributed with reagents and mouse lines. FXR contributed to experimental design, conceived and supervised the study. LR and FXR wrote the paper with contributions from the co-authors. FXR and AR obtained financial support.

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Correspondence to Francisco X. Real.

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Richart, L., Felipe, I., Delgado, P. et al. Bptf determines oncogenic addiction in aggressive B-cell lymphomas. Oncogene 39, 4884–4895 (2020). https://doi.org/10.1038/s41388-020-1331-3

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