Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma

Abstract

Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed biologically and prognostically distinct subgroups: germinal center B-cell-like (GCB), activated B-celllike (ABC) and primary mediastinal (PM) DLBCL. The BCL6 gene is often translocated and/or mutated in DLBCL. Therefore, we examined the BCL6 molecular alterations in these DLBCL subgroups, and their impact on BCL6 expression and BCL6 target gene repression. BCL6 translocations at the major breakpoint region (MBR) were detected in 25 (18.8%) of 133 DLBCL cases, with a higher frequency in the PM (33%) and ABC (24%) subgroups than in the GCB (10%) subgroup. Translocations at the alternative breakpoint region (ABR) were detected in five (6.4%) of 78 DLBCL cases, with three cases in ABC and one case each in the GCB and the unclassifiable subgroups. The translocated cases involved IgH and non-IgH partners in about equal frequency and were not associated with different levels of BCL6 mRNA and protein expression. BCL6 mutations were detected in 61% of DLBCL cases, with a significantly higher frequency in the GCB and PM subgroups (470%) than in the ABC subgroup (44%). Exon-1 mutations were mostly observed in the GCB subgroup. The repression of known BCL6 target genes correlated with the level of BCL6 mRNA and protein expression in GCB and ABC subgroups but not with BCL6 translocation and intronic mutations. No clear inverse correlation between BCL6 expression and p53 expression was observed. Patients with higher BCL6 mRNA or protein expression had a significantly better overall survival. The biological role of BCL6 in translocated cases where repression of known target genes is not demonstrated is intriguing and warrants further investigation.

Diffuse large B-cell lymphomas with CDKN2A deletion have a distinct gene expression signature and a poor prognosis under R-CHOP treatment: a GELA study

“…[33][34][35] More recently, it was demonstrated that inactivation of TP53 was associated with a particular GEP characterized notably by a decreased expression of TRAIL receptor-2. 26 Here, we delineated approximately 100 genes that distinguish DLBCL 9p21del .…”

Most primary adrenal lymphomas are diffuse large B-cell lymphomas with non-germinal center B-cell phenotype, BCL6 gene rearrangement and poor prognosis

“…[12][13][14][15] It is more frequently detected in diffuse large B-cell lymphomas with an activated Bcell/non-germinal center B-cell phenotype than in those with a germinal center B-cell phenotype. 16,17 The significance of BCL6 gene rearrangement in disease presentation and survival is controversial. Using Southern blot analysis, Offit et al 13 Primary adrenal lymphoma A Mozos et al between BCL6 rearrangement and initial features of the disease or clinical outcome.…”

Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance

“…However, p53 mutations are observed after chemotherapy of various hematopoietic malignancies. [50][51][52][53][54][55][56] The interactions between the p53 and Ras/Raf/MEK/ERK pathways are complex and a focal point in the sensitivity of cells to chemotherapeutic drugs such as doxorubicin. Doxorubicin, through reactive oxygen species and other molecular mechanisms, may induce p53, which in turn promotes the expression of pro-apoptotic genes, such as Noxa and Puma.…”