Molecular Dissection of Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL), the most common form of human lymphoma, is an aggressive malignancy comprising multiple phenotypically and genetically distinct subtypes, approximately 40% of which are incurable. These tumors may arise de novo or from the transformation of more indolent lymphomas, as observed in 30-40% of follicular lymphoma (FL) and 5-12% of chronic lymphocytic leukemia cases. Over the last decade, the introduction of next-generation sequencing technologies combined with genome-wide copy number analysis has allowed a comprehensive definition of the genetic lesions that are associated with the pathogenesis of these malignancies, leading to the identification of several previously unappreciated targets^1-3. These lesions, in turn, uncovered dysregulated cellular pathways that represent potential targets for improved diagnosis and therapy. Among the most common genetic alterations found in both de novo DLBCL and transformed FL (tFL) are those targeting histone/chromatin modifiers; in particular, loss-of-function mutations in the genes encoding for the H3K4 methyltransferase MLL2 and the acetyltransferases CREBBP/EP300, together with gain-of-function mutations of the EZH2 H3K27 methyltransferase are observed in over 50% of DLBCL and 90% of tFL patients, suggesting a major role for these enzymes in altering gene expression during malignant transformation. Interestingly, sequential analysis of tumor samples isolated at FL diagnosis and at evolution to DLBCL indicates that inactivating mutations of CREBBP and MLL2 represent early events acquired during the initial expansion of a common ancestral clone⁴. Disruption of epigenetic modifiers by genetic alterations may thus contribute to malignant transformation by shaping the epigenetic landscape of the cancer cell as well as by perturbing specific biological programs. In line with this hypothesis, we have shown that mutations of CREBBP/EP300 disrupt the balance between acetylation-mediated activation of the p53 tumor suppressor and inactivation of the BCL6 proto-oncogene⁵. The lecture will cover recent advances in our understanding of the genetic basis of this disease, with emphasis on the role of epigenetic regulators in normal germinal center development and lymphomagenesis, as revealed by in vitro and in vivo studies.

References:

1. Pasqualucci L, Trifonov V, Fabbri G, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet. 2011; 43: 830-837.

2. Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011; 476: 298-303.

3. Lohr JG, Stojanov P, Lawrence MS, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A. 2012; 109: 3879-3884.

4. Pasqualucci L, Khiabanian H, Fangazio M, et al., Genetics of follicular lymphoma transformation. Cell Rep. 2014; 6:130-140.

5. Pasqualucci L, Dominguez-Sola D, Trifonov V, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011; 471: 189-195.