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Lymphoma

Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma

Leukemia volume 31, pages 625–636 (2017)Cite this article

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Abstract

PRDM1/BLIMP-1, a master regulator of plasma-cell differentiation, is frequently inactivated in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) patients. Little is known about its genetic aberrations and relevant clinical implications. A large series of patients with de novo DLBCL was effectively evaluated for PRDM1/BLIMP-1 deletion, mutation, and protein expression. BLIMP-1 expression was frequently associated with the ABC phenotype and plasmablastic morphologic subtype of DLBCL, yet 63% of the ABC-DLBCL patients were negative for BLIMP-1 protein expression. In these patients, loss of BLIMP-1 was associated with Myc overexpression and decreased expression of p53 pathway molecules. In addition, homozygous PRDM1 deletions and PRDM1 mutations within exons 1 and 2, which encode for domains crucial for transcriptional repression, were found to show a poor prognostic impact in patients with ABC-DLBCL but not in those with germinal center B-cell-like DLBCL (GCB-DLBCL). Gene expression profiling revealed that loss of PRDM1/BLIMP-1 expression correlated with a decreased plasma-cell differentiation signature and upregulation of genes involved in B-cell receptor signaling and tumor-cell proliferation. In conclusion, these results provide novel clinical and biological insight into the tumor-suppressive role of PRDM1/BLIMP-1 in ABC-DLBCL patients and suggest that loss of PRDM1/BLIMP-1 function contributes to the overall poor prognosis of ABC-DLBCL patients.

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Acknowledgements

This study was supported by grants from the National Institutes of Health/National Cancer Institute (R01CA138688 and 1RC1CA146299 to YL and KHY). YX is a recipient of a hematology and oncology scholarship award. AT was supported by the Krebsliga Beider Basel and Stiftung zur Krebsbekaempfung Zurich. KHY was supported by The University of Texas MD Anderson Cancer Center Lymphoma Moon Shot Program, the Institutional Research and Development Fund, an MD Anderson Institutional Research Grant, an MD Anderson Lymphoma Specialized Program of Research Excellence Research Development Program Award, an MD Anderson Myeloma Specialized Program of Research Excellence Research Development Program Award and a Gundersen Medical Foundation award. In addition, the study was partially supported by grants from the National Institutes of Health/National Cancer Institute (P50CA136411 and P50CA142509) and by the National Institutes of Health/National Cancer Institute under award number P30CA016672. KHY receives research support from Roche Molecular Systems, Gilead Sciences, Seattle Genetics, Daiichi Sankyo, Adaptive Biotechnologies, Incyte and HTG Molecular Diagnostics.

Author information

Author notes

  1. Y Xia, Z Y Xu-Monette and A Tzankov: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Y Xia, Z Y Xu-Monette, X Li, S Zhang, R N Miranda, C Y Ok, L J Medeiros & K H Young

  2. The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China

    Y Xia & J Li

  3. University Hospital, Basel, Switzerland

    A Tzankov

  4. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G C Manyam

  5. Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA

    V Murty, G Bhagat & L Pasqualucci

  6. San Bortolo Hospital, Vicenza, Italy

    C Visco

  7. Aalborg University Hospital, Aalborg, Denmark

    K Dybkaer

  8. Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    A Chiu

  9. Weill Medical College of Cornell University, New York, NY, USA

    A Orazi

  10. The Methodist Hospital, Houston, TX, USA

    Y Zu

  11. Cornell University, Ithaca, NY, USA

    K L Richards

  12. Cleveland Clinic, Cleveland, OH, USA

    E D Hsi

  13. University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China

    W W L Choi

  14. Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands

    J H van Krieken

  15. Asan Medical Center, Ulsan University College of Medicine, Seoul, South Korea

    J Huh

  16. San Raffaele H. Scientific Institute, Milan, Italy

    M Ponzoni & A J M Ferreri

  17. Odense University Hospital, Odense, Denmark

    M B Møller

  18. Gundersen Lutheran Health System, La Crosse, WI, USA

    B M Parsons

  19. Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    J N Winter

  20. Hospital Universitario Marqués de Valdecilla, Santander, Spain

    M A Piris

  21. Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Westin & N Fowler

  22. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Y Li

  23. The University of Texas School of Medicine, Graduate School of Biomedical Sciences, Houston, TX, USA

    K H Young

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Xia, Y., Xu-Monette, Z., Tzankov, A. et al. Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma. Leukemia 31, 625–636 (2017). https://doi.org/10.1038/leu.2016.243

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