MYC in Germinal Center-derived lymphomas: Mechanisms and therapeutic opportunities

Abstract

The rearrangement of immunoglobulin loci during the germinal center reaction is associated with an increased risk of chromosomal translocations that activate oncogenes such as MYC, BCL2 or BCL6, thus contributing to the development of B-cell lymphomas. MYC and BCL2 activation are initiating events in Burkitt's (BL) and Follicular Lymphoma (FL), respectively, but can occur at later stages in other subtypes such as Diffuse Large-B Cell Lymphoma (DLBCL). MYC can also be activated during the progression of FL to the transformed stage. Thus, either DLBCL or FL can give rise to aggressive double-hit lymphomas (DHL) with concurrent activation of MYC and BCL2. Research over the last three decades has improved our understanding of the functions of these oncogenes and the basis for their cooperative action in lymphomagenesis. MYC, in particular, is a transcription factor that contributes to cell activation, growth and proliferation, while concomitantly sensitizing cells to apoptosis, the latter being blocked by BCL2. Here, we review our current knowledge about the role of MYC in germinal center B-cells and lymphomas, discuss MYC-induced dependencies that can sensitize cancer cells to select pharmacological inhibitors, and illustrate their therapeutic potential in aggressive lymphomas-and in particular in DHL, in combination with BCL2 inhibitors.

Keywords: B-cell lymphoma; BCL2; Germinal Center; MYC; Tigecycline; Venetoclax.