Anti-C-Myc polyclonal antibody, FITC

The human genome project revealed the existence of many thousands of long non-coding RNAs (lncRNAs). These transcripts that are over 200 nucleotides long were soon recognized for their importance in regulating gene expression. However, their poor conservation among species and their still controversial annotation has limited their study to some extent. Moreover, a generally lower expression of lncRNAs as compared to protein coding genes and their enigmatic biochemical mechanisms have impeded progress in the understanding of their biological roles. It is, however, known that lncRNAs engage in various kinds of interactions and can form complexes with other RNAs, with genomic DNA or proteins rendering their functional regulatory network quite complex. It has emerged from recent studies that lncRNAs exert important roles in gene expression that affect many cellular processes underlying development, cellular differentiation, but also the pathogenesis of blood cancers like leukemia and lymphoma. A number of lncRNAs have been found to be regulated by several well-known transcription factors including Myelocytomatosis viral oncogene homolog (MYC). Thec-MYCgene is known to be one of the most frequently deregulated oncogenes and a driver for many human cancers. The c-MYCgene is very frequently activated by chromosomal translocations in hematopoietic cancers most prominently in B- or T-cell lymphoma or leukemia and much is already known about its role as a DNA binding transcriptional regulator. Although the understanding of MYC's regulatory role controlling lncRNA expression and howMYCitself is controlled by lncRNA in blood cancers is still at the beginning, an intriguing picture emerges indicating thatc-MYCmay execute part of its oncogenic function through lncRNAs. Several studies have identified lncRNAs regulating c-MYCexpression andc-MYCregulated lncRNAs in different blood cancers and have unveiled new mechanisms how these RNA molecules act. In this review, we give an overview of lncRNAs that have been recognized as critical in the context of activatedc-MYCin leukemia and lymphoma, describe their mechanism of action and their effect on transcriptional reprogramming in cancer cells. Finally, we discuss possible ways how an interference with their molecular function could be exploited for new cancer therapies.

Simple Summary A diagnosis of diffuse large B-cell lymphoma in our therapeutic era should be implemented by the definition of the cell of origin, additional immunohistochemistry (i.e., BCL2 and MYC), and by fluorescent in-situ hybridization. The next step, suggested by the seminary works we will discuss in this review, will be to implement the definition of sub-categories by the recognition of single gene mutations and pathways that may be targetable by newer drugs. We here describe the impact that MYD88 and CD79B activating mutations, two of the most frequent mutations in several DLBCL subtypes, may achieve in the next future in the diagnosis and therapeutics of such a relevant lymphoma subtype. Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma in adults. Despite the recognition of transcriptional subtypes with distinct functional characteristics, patient outcomes have not been substantially altered since the advent of chemoimmunotherapy (CIT) twenty years ago. Recently, a few pivotal studies added to the disease heterogeneity by describing several activating mutations, which have been associated with disease presentation, B-cell function and behavior, and final outcome. DLBCL arises from antigen exposed B-cells, with the B-cell receptor (BCR) playing a central role. BCR-activity related mutations, such as CD79B and MYD88, are responsible for chronic activation of the BCR in a substantial subset of patients. These mutations, often coexisting in the same patient, have been found in a substantial subset of patients with immune-privileged (IP) sites DLBCLs, and are drivers of lymphoma development conferring tissue-specific homing properties. Both mutations have been associated with disease behavior, including tumor response either to CIT or to BCR-targeted therapy. The recognition of CD79B and MYD88 mutations will contribute to the heterogeneity of the disease, both in recognizing the BCR as a potential therapeutic target and in providing genetic tools for personalized treatment.