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

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.

Figure 1

Homozygous PRDM1 deletion in DLBCL cases. (a) Representative examples of FISH results with heterozygous PRDM1 deletion (of note are a mixture of cells with two green signals, corresponding to centromere 6, but lacking red signals, corresponding to PRDM1, and cells with two green signals and one red signal), homozygous PRDM1 deletion (of note are two green signals but a lack of red signals in the majority of the cells; one cell in the center of the microphotograph has both red and green signals and serves as an internal positive control), and monosomy 6 (all cells have only one green and one red signal). DLBCL patients with homozygous PRDM1 deletions had lower levels of BLIMP-1 protein expression than did the rest of the studied patients. (b–c) The impact of homozygous PRDM1 deletion on OS and PFS in all patients with DLBCL, patients with ABC-DLBCL, and patients with GCB-DLBCL. Patients with this deletion had shorter OS and PFS durations than did patients with normal FISH signals, heterozygous PRDM1 deletions, or monosomy 6. This trend was greater in patients with ABC-DLBCL than in GCB-DLBCL.

Figure 2

Correlation of PRDM1 mutations with poor prognosis for DLBCL. (a) In ABC-DLBCL, patients with PRDM1 mutations had shorter OS and PFS durations than did patients with wild-type PRDM1. (b) PRDM1 mutations within exons 1 and 2 had even greater poor impact on OS and PFS compared to did the overall mutation cohort. (c) The detailed distribution of PRDM1 mutations within exons 1 and 2.

Figure 3

BLIMP-1 protein expression in DLBCL. (a) Representative immunohistochemical stains of DLBCL sections for BLIMP-1 protein expression. (b) The histograms of BLIMP-1 protein expression in all DLBCL patients, and the distribution of PRDM1 deletions and mutations and BLIMP-1 protein expression in 180 patients with all these three data available. Expression of miR-30d-3p and miR-30b-5p was elevated in BLIMP-1⁻ DLBCL patients without PRDM1 genetic alterations. (c) The impact of BLIMP-1 protein expression on OS and PFS in DLBCL patients with mutated TP53.

Figure 4

Gene expression profiles for the overall and ABC-DLBCL patients and the BLIMP-1 network in DLBCL. (a) Differential expression of genes between patients with and without homozygous PRDM1 deletions, and between patients with and without BLIMP-1 protein expression. Differential expression of genes were only found between wild-type BLIMP-1⁺ and BLIMP-1⁻ DLBCLs but not between mutated BLIMP-1⁺ and BLIMP-1⁻ DLBCLs. (b) A brief network of BLIMP-1’s functions and regulations summarizing our results. BLIMP-1 can be activated by p53, IRF4, and NF-κB signaling. BLIMP-1 represses the transcription of MYC, B-cell antigen/surface receptors, and germinal center programs, whereas activates LAX1 which inhibits B-cell receptor (BCR) signaling, therefore leading to attenuated BCR signaling and decreased tumor cell proliferation. BLIMP-1 also transactivates XBP1 and ELL2, which results in activation of plasmacytic differentiation and immunoglobulin production.