On April 5 th2017, during this year’s American Association for Cancer Research (AACR) annual meeting, Laura Pasqualucci, from Columbia University, New York, gave a presentation on the topic of “ Novel therapeutic opportunities for germinal center B-cell lymphomas”. This presentation was part of the session titled “ Novel Targets in Hematologic Malignancies”.
Professor Pasqualucci began her talk by explaining that DLBCL has “remarkable heterogeneity in morphologic, molecular, and clinical features”, and outlined the recognized phenotypic subgroups of DLBCL as being GCB-DLBCL, ABC-DLBCL, and PMBCL. The GCB- and ABC-DLBCL subtypes share common aberrant molecular pathways such as deregulation of BCL6, however, they have major differences in other pathways which were highlighted on this slide:
Epigenetics and transcriptional modification also play different roles in different lymphoma subtypes. Below is an overview of some of the known changes to epigenetic and transcriptional proteins; of note is that 25% of DLBCL cases have mutations in CREBBP or EP300, and 30% have mutations in MLL2, part of the COMPASS complex which de-condenses chromatin.
The mutations in MLL2 and CREBBP have been shown to result in protein truncation at the C-terminus, which is where the catalytic domain of these proteins reside, thereby resulting in impaired protein function. Datawas also shownthat suggested that these mutations are monoallelic, potentially meaning that they have a haploinsufficient tumor suppressor function.
In 2015, using mouse models, it was found that MLL2 loss resulted in perturbed formation of germinal centers, and was found to be able to cooperate with BCL2 deregulation in FL and DLBCL lymphomas, as shown by BCL2 overexpressing mice who had MLL2 genetic ablation.
Professor Pasqualucci next spoke about the role of inactivating CBP (CREB-binding protein)/p300 in DLBCL and FL. She stated that inactivation of CBP/p300 relieves the inactivation of BCL6, allowing it to inhibit p53, resulting in lower p53 activation. As p53 is a tumor suppressor, its reduced activation may contribute to oncogenesis.
Data presented based on a variety of transcriptional analyses showed that CBP regulates a network of proteins involved with BCR, NFkB, and Toll-like receptor signaling, in addition to signaling involved with lymphocyte motility.
Professor Pasqualucci next went on to detail data that showed that CBP is involved with activating targets which are typically repressed by BCL6. The BCL6-repressed targets function in a variety of cellular processes including apoptosis, differentiation, and cell cycle regulation. Furthermore, it was shown that loss of a single allele of CBP resulted in B-cell lymphoma development via BCL2 (below).
In summary, Professor Pasqualucci summarized that the role of CBP/p300 is to orchestrate key cellular processes through interaction with key transcription factors. However, when the activation of CBP/p300 is limited in germinal center cells, many downstream pathways are altered, resulting in aberrant cell behavior and, potentially, lymphomagenesis. In the future, targeting these pathways may help bring about new drugs to treat lymphomas where these mutations have occurred.