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

Y. Xia, Z. Y. Xu-Monette, A. Tzankov, X. Li, G. C. Manyam, V. Murty, G. Bhagat, S. Zhang, L. Pasqualucci, C. Visco, K. Dybkaer, A. Chiu, A. Orazi, Y. Zu, K. L. Richards, E. D. Hsi, W. W.L. Choi, J. H. Van Krieken, J. Huh, M. PonzoniA. J.M. Ferreri, M. B. Møller, B. M. Parsons, J. N. Winter, M. A. Piris, J. Westin, N. Fowler, R. N. Miranda, C. Y. Ok, Y. Li, J. Li, L. J. Medeiros, K. H. Young*

*Corresponding author for this work

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)625-636
Number of pages12
JournalLeukemia
Volume31
Issue number3
DOIs
StatePublished - Mar 1 2017

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ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Xia, Y., Xu-Monette, Z. Y., Tzankov, A., Li, X., Manyam, G. C., Murty, V., Bhagat, G., Zhang, S., Pasqualucci, L., Visco, C., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Richards, K. L., Hsi, E. D., Choi, W. W. L., Van Krieken, J. H., Huh, J., ... Young, K. H. (2017). Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma. Leukemia, 31(3), 625-636. https://doi.org/10.1038/leu.2016.243