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

Y Xia, ZY Xu-Monette, A Tzankov, X Li, GC Manyam, V Murty, G Bhagat, S Zhang, L Pasqualucci, C Visco, K Dybkaer, April Chiu, Attilio Orazi, Y Zu, KL Richards, ED Hsi, WW Choi, JH van Krieken, J Huh, M PonzoniAJ Ferreri, MB Møller, BM Parsons, JN Winter, MA Piris, J Westin, N Fowler, RN Miranda, CY Ok, Y Li, J Li, LJ Medeiros, KH Young

Research output: Contribution to journalArticlepeer-review

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
Pages (from-to)625-636
Number of pages12
JournalLeukemia
Volume31
Issue number3
DOIs
Publication statusPublished - 2017

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