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

Xia, Y.; Xu-Monette, Z. Y.; Tzankov, A.; Li, X.; Manyam, G. C.; Vundavalli, Murty V.; Bhagat, Govind; Zhang, S.; Pasqualucci, Laura; 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.; Ponzoni, M.; Ferreri, A. J. M.; Møller, M. B.; Parsons, B. M.; Winter, J. N.; Piris, M. A.; Westin, J.; Fowler, N.; Miranda, R. N.; Ok, C. Y.; Li, Y.; Li, J.; Medeiros, L. J.; Young, K. H.

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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Pathology and Cell Biology
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August 27, 2019