c-Myc overexpression promotes a germinal center-like program in Burkitt's lymphoma

Abstract

The germinal center (GC) reaction has a pivotal function in human B-cell lymphomagenesis. Genetic aberrations occurring during somatic hypermutation and class switch recombination deregulate key factors controlling B-cell physiology and proliferation. Several human lymphoma entities are characterized by a constitutive GC phenotype and ongoing somatic hypermutation, but the molecular basis for this phenomenon is only partly understood. We have investigated the reasons for a constitutive GC-like program in Burkitt's lymphoma cells. Here, overexpression of c-Myc leads to a centroblast phenotype, promotes high constitutive expression of the key GC factors Bcl-6, E2A and activation-induced cytidine deaminase and contributes to proliferation and somatic hypermutation. Our findings elucidate how the activity of a pivotal transcription factor may freeze B-cell lymphoma cells in a constitutive GC-like state that is even maintained at an extrafollicular location.

CD300a is expressed on human B cells, modulates BCR-mediated signaling, and its expression is down-regulated in HIV infection

“…Burkitt lymphoma is the prototypic GC-like lymphoma 27 and, in agreement with our results on CD300a expression by GC cells, we found that, except for the BJAB cell line that expresses low amounts of CD300a, the rest of the Burkitt lymphoma cell lines (n ϭ 7) are negative for CD300a expression. On the other hand, the non-Hodgkin lymphoma cell lines REC-1 (mantle cell lymphoma) and SUDHL5 (diffuse large B-cell lymphoma with ABC-like phenotype) are positive for CD300a expression, which is in agreement with the origin of these lymphomas, namely, pre-GC B cells and activated B cells, respectively.…”

Regulation of memory B-cell survival by the BH3-only protein Puma

“…It has recently been shown that c-Myc overexpression is responsible for the "centroblast-like" phenotype of the Burkitt lymphoma cells and that treatment of these cells with a specific c-Myc inhibitor, 10058-F4 inhibits expression of proteins associated with the germinal center phenotype, such as Bcl-6. 31 We therefore explored whether the modification of this "germinal center phenotype" was also associated with a change in the regulation of Puma expression. Indeed, we observed a parallel decrease in the levels of Bcl-6 and Puma proteins from BL41 cells in response to treatment with various doses of 10058-F4, whereas the levels of Bcl-2 or GAPDH were not altered ( Figure 2D).…”

Critical role of SHP2 (PTPN11) signaling in germinal center-derived lymphoma

“…Our work has also led to the discovery of a SHP2-dependent GC lymphoma proliferative signature comprising a set of genes that are overexpressed in GC lymphomas. 5,6 Depletion of SHP2 led to a similar impairment of GC lymphoma proliferative phenotype signature expression, demonstrating that SHP2 is a high-quality target in GC lymphomas.…”

“…In addition, our data indicate that SHP2 activation of ERK1/2 might be responsible for the transcriptional activation of c-Myc, which mediates an increase in the expression of "GC lymphoma phenotype proteins". 5,6 SHP2/ERK signaling mediated c-Myc Ser62 phosphorylation thus stabilizing c-Myc protein and enhancing its transcriptional activity. 19,30 Conversely, ERK activation phosphorylates GSK3b Ser389 in the C-terminus, which causes GSK3b inactivation and inhibits c-Myc Thr58 phosphorylation from mediating c-Myc proteolysis.…”

“…3 Thus, the beneficial features of GC B cells are, to some extent, counterbalanced by their potential adverse roles in lymphomagenesis because the majority of malignant lymphomas derive from GC B cells (GC lymphoma). 4,5 Prototypic examples include the translocation which places oncogenic MYC under the control of the IGH promoter in Burkitt lymphoma 6 and some diffuse large B-cell lymphomas 7 as well as the BCL2/IGH translocation in follicular lymphoma and GC B-cell-like diffuse large B-cell lymphoma. 8 The entry of B cells into the GC requires stimulation by foreign pathogens through both BCR/CD19/CD21 9 and antigenspecific T helper cell/CD40L/CD40 signals.…”