BLIMP1 and Lymphomas

Different evidences, among which the frequent loss of the genomic region 6q21 encompassing PRDM1 gene, suggest that an abnormal regulation or an abnormal activity of BLIMP1 may be one causal event in some B cells and NK cells malignancies. If this transcription factor acts as a tumor suppressor, lack of its function could be important in development of some forms of lymphomas. However, loss of BLIMP1 alone is not sufficient for B cells lymphomagenesis, as inferred from mice with conditional deletion of PRDM1 in the B cell lineage which do not develop B cell tumors spontaneously [189].

Nevertheless, more and more studies recently reported the frequent inactivation of

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BLIMP1, through deletion or mutation, in different lymphoma subtypes, providing evidence that it may indeed functions as a tumor suppressor gene.

In 2006, two different groups [49, 216], after the observation of the frequent loss at genomic locus 6q21, identified BLIMP1 inactivation by structural alterations in approximately 24% of DLBCL cases analyzed. Interestingly, all of these cases were restricted to the ABC-DLBCL subtype, suggesting a role for this gene in this particular B cell lymphoma subtype. Nor GCB-DLBCL cases or unclassified cases have been reported to show inactivation of BLIMP1. The alterations observed in these studies included gene truncations, nonsense mutations, frameshift deletions and splice site mutations that leaded to the generation of aberrant transcripts encoding truncated BLIMP1 proteins. Moreover, in all cases, both BLIMP1 alleles were inactivated by deletion or mutations. These results suggest that BLIMP1 inactivation follows the typical two-hit mechanisms in different ABC-DLBCL cases, strongly suggesting that BLIMP1 may act as a tumor suppressor gene, whose loss of function may be critical for the pathogenesis of ABC-DLBCL. More recently the group of Laura Pasqualucci [50] reported further data on the role of BLIMP1 in DLBCL: converging evidences from human genetics, functional studies and mouse models indicated that BLIMP1 must be considered a bona fide tumor suppressor gene for ABC-DLBCL, in which the gene inactivation contributes to lymphomagenesis by blocking plasma cells differentiation. In this report, BLIMP1 was inactivated in 53% of ABC-DLBCL cases analyzed by multiple mechanisms, such as deletions, homozygous deletions, truncating or missense mutations and transcriptional repression by BCL6, which was observed to be translocated and so constitutively active in many cases. BCL6 aberrations and BLIMP1 inactivation appear mutually exclusive. Analysis of 6q21 deletions revealed, also in this cohort of samples, that the majority of the mutated cases had lost expression of the wild type allele due to deletion, epigenetic silencing or UPD, demonstrating biallelic inactivation of the gene. As in the previous study of the group, also in this analysis, a moderate percentage of ABC-DLBCL cases showed no alteration at BLIMP1 or BCL6 levels, but lacked BLIMP1 protein, despite the presence of IRF4, a transcriptional repressor that is known to be invariably coexpressed with BLIMP1 in normal GC B cells and in all plasma cells. This phenomenon suggests that other mechanisms, such as for example promoter hypermethylation, could be responsible for the absence of BLIMP1 protein. Functional studies performed with the re-introduction of BLIMP1 into a DLBCL cell line, suggest the central role of this gene in the block of terminal differentiation and in the modulation of

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expression of genes involved in cell cycle progression. Other studies in mouse models, confirmed that BLIMP1 disruption promotes the development of lymphomas often resembling human ABC-DLBCL, but, since the low penetrance, long latency and clonality of DLBCL in these mice, it has been suggested that additional oncogenic events are required for the pathogenesis of this disease [217]. Constitutive activation of the canonical NF-κB pathway, which is also a typical feature of human ABC-DLBCL, strongly synergized with BLIMP1 loss in lymphomagenesis, suggesting that both NF-κB signaling and BLIMP1 loss play critical roles in the pathogenesis of ABC-DLBCL [217].

Two years ago, PRDM1 has been reported to be a gene with a tumor suppressor function in Natural Killer Cell Lymphoma (NKCL) as well [91, 92]. In both cases, array-CGH analysis highlighted 6q21 loss as one of the most frequent aberration identified in clinical specimens and cell lines. In the study of Karube et al [91], the two narrow regions inside the 6q21 loss include different genes, among which PRDM1 and FOXO3. Forced re-expression of BLIMP1 and FOXO3 leaded to the suppression of cell proliferation in both cases with a concomitant induction of apoptosis and cell-cycle arrest. The genomic analysis for the presence of mutations inside these two genes revealed that only one or two cases (one clinical specimen and one cell line) for FOXO3 and BLIMP1 respectively, presented a genomic mutation accompained by the genomic loss of the gene, considering the idea of a biallelic inactivation. For the other cases, in which only heterozygous genomic loss is observed, haploinsufficiency has been suggested as the mechanism responsible for gene inactivation. In both cases, functional studies suggest a tumor suppressor role for these genes. Moreover, PRDM1 gene has been reported to be inactivated by a combination of deletion and promoter hypermethylation [92] in NKCL. In support of its role as a tumor suppressor gene, the reconstitution of BLIMP1 in NKCL cell lines led to G2/M cell-cycle arrest, increased apoptosis and a strong negative selection pressure with progressive elimination of BLIMP1-expressing cells. In conclusion, recent and numerous evidences suggest that PRDM1/BLIMP1 could act as a tumor suppressor gene in different types of lymphoma, deriving from B and NK cells, and have a role in the pathogenesis of these neoplastic diseases. For this reason, the study of this gene in other malignancies, especially in other lymphoma subtypes, could improve the understanding of the role of this gene in the pathogenesis. If BLIMP1 exherts a role in lymphomagenesis in different type of lymphomas, deriving also from different cells of origin, could be of great interest to try to develop different thrapeutic strategies which allow the reintroduction of BLIMP1 gene in tumor cells. This putative target therapy could be helpful

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in association with the conventional ones which very often are not sufficient for the healing of patients.

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