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.

Flow Cytometric Methods for the Detection of Intracellular Signaling Proteins and Transcription Factors Reveal Heterogeneity in Differentiating Human B Cell Subsets

“…The ability to monitor both this signaling and transcriptional regulation is necessary to enable fundamental research on wanted B cell responses against pathogens and unwanted B cell responses, as observed in autoimmune diseases [37][38][39] or during allo-antibody formation after blood transfusion [40]. Additionally, transcriptional dysregulation and overactivated signaling pathways can lead to B cell malignancies [41,42]. Finally, it can aid in the development and characterization of therapeutic inhibitors for a range of diseases [43].…”

Flow Cytometric Methods for the Detection of Intracellular Signaling Proteins and Transcription Factors Reveal Heterogeneity in Differentiating Human B Cell Subsets

“…The ability to monitor both this signaling and transcriptional regulation is necessary to enable fundamental research on wanted B cell responses against pathogens and unwanted B cell responses as observed in autoimmune diseases [38][39][40] or during allo-antibody formation after blood transfusion [41]. Additionally, transcriptional dysregulation and overactivated signaling pathways can lead to B cell malignancies [42,43]. Finally, it can aid in the development and characterization of therapeutic inhibitors for a range of diseases [44].…”

Impact of MYC on Anti-Tumor Immune Responses in Aggressive B Cell Non-Hodgkin Lymphomas: Consequences for Cancer Immunotherapy

“…MYC promotes B cell proliferation and differentiation by activating several B cell determining genes, such as Cd19 [ 33 , 34 , 35 , 36 , 37 ]. Immature B cells expressing a complete, functional, non-autoreactive BCR downregulate MYC expression, enter the peripheral circulation and then accumulate in lymph nodes where further maturation takes place under differential MYC expression [ 38 , 39 ]. MYC is re-expressed after (antigen) activation of the BCR, promoting proliferation and inhibiting differentiation of mature B cells [ 39 , 40 ].…”

“…Immature B cells expressing a complete, functional, non-autoreactive BCR downregulate MYC expression, enter the peripheral circulation and then accumulate in lymph nodes where further maturation takes place under differential MYC expression [ 38 , 39 ]. MYC is re-expressed after (antigen) activation of the BCR, promoting proliferation and inhibiting differentiation of mature B cells [ 39 , 40 ]. After positive selection, MYC expression is downregulated, allowing B cells to differentiate into memory B cells or plasmablasts and to exit the germinal center [ 39 , 41 ].…”

“…MYC is re-expressed after (antigen) activation of the BCR, promoting proliferation and inhibiting differentiation of mature B cells [ 39 , 40 ]. After positive selection, MYC expression is downregulated, allowing B cells to differentiate into memory B cells or plasmablasts and to exit the germinal center [ 39 , 41 ]. In plasmablasts, MYC expression is suppressed, allowing terminal B cell differentiation into plasma cells [ 42 ].…”