MYC alterations in diffuse large B-cell lymphomas

Abstract

MYC is a transcription factor associated with numerous physiological functions, including apoptosis, and strong oncogenic potential. MYC expression is tightly regulated in normal lymphoid cells with high levels in the initial steps of the secondary lymphoid follicle formation and in a subset of centrocytes of the germinal center light zone. BCL6 and BLIMP1 repress MYC expression in normal germinal center B and plasma cells, respectively. Paradoxically, most lymphomas with MYC genetic alterations originate from cells that usually do not express MYC, suggesting that these tumors need to develop additional oncogenic events to overcome the MYC regulatory mechanisms and also its proapoptotic function. MYC rearrangements, and to a lesser extent gene amplifications, have been detected in approximately 5% to 14% of diffuse large B-cell lymphoma (DLBCL) and these alterations are frequently associated with BCL2 or BCL6 rearrangements. The concurrent presence of these alterations confers a more aggressive behavior to the tumors with poor outcome of the patients. BCL2 and MYC protein may also be coexpressed in DLBCL independently of gene alterations and this double expression also confers poor prognosis, although not as dismal as that of double genetic hits. Additional factors may modulate the biological effect of the double hit lesions because tumors in which MYC is translocated to non-IGH partner or MYC and BCL2 protein that are expressed at lower levels may have a less aggressive behavior. Further studies are needed to define the clinical implications of MYC aberrations in DLBCL and determine the most appropriate diagnostic strategy to identify these tumors.