MYC's Fine Line Between B Cell Development and Malignancy

Abstract

The transcription factor MYC is transiently expressed during B lymphocyte development, and its correct modulation is essential in defined developmental transitions. Although temporary downregulation of MYC is essential at specific points, basal levels of expression are maintained, and its protein levels are not completely silenced until the B cell becomes fully differentiated into a plasma cell or a memory B cell. MYC has been described as a proto-oncogene that is closely involved in many cancers, including leukemia and lymphoma. Aberrant expression of MYC protein in these hematological malignancies results in an uncontrolled rate of proliferation and, thereby, a blockade of the differentiation process. MYC is not activated by mutations in the coding sequence, and, as reviewed here, its overexpression in leukemia and lymphoma is mainly caused by gene amplification, chromosomal translocations, and aberrant regulation of its transcription. This review provides a thorough overview of the role of MYC in the developmental steps of B cells, and of how it performs its essential function in an oncogenic context, highlighting the importance of appropriate MYC regulation circuitry.

Keywords: B cell development; MYC; leukemia; lymphoma.

Figure 1

Expression and role of MYC in B lymphocyte differentiation. Schematic representation of the participation of the MYC protein throughout B-cell differentiation in the bone marrow and germinal center (GC). The percentages shown refer to the population of MYC⁺, BCL6^+/− cells in the total number of B cells present in the GC. The blue-colored line at the top of the Figure indicates the evolution of MYC expression, where darker blue indicates steps that require higher MYC levels.

Figure 2

Activating mechanisms of c-MYC in leukemia with the BCR-ABL1 rearrangement. A summary of the different transduction signaling pathways that trigger the activation of MYC promoter in BCR-ABL1-rearranged leukemia. Apart from direct transcriptional activation pathways, marked in green, alternative mechanisms that induce c-MYC are depicted in black and highlighted in black squares. Dashed arrows indicate the translocation of proteins between the nucleus and the cytoplasm.