Insights about MYC and Apoptosis in B-Lymphomagenesis: An Update from Murine Models.

Eleonora Vecchio,Serena Correnti,Ileana Quinto,Salvatore Romano,Nancy Nisticò,Giuseppe Fiume,Domenico Maisano,Selena Mimmi,Enrico Iaccino

doi:10.3390/ijms21124265

Eleonora Vecchio, Serena Correnti + Show 7 more

Open Access

https://doi.org/10.3390/ijms21124265

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Abstract

The balance between cell survival and cell death represents an essential part of human tissue homeostasis, while altered apoptosis contributes to several pathologies and can affect the treatment efficacy. Impaired apoptosis is one of the main cancer hallmarks and some types of lymphomas harbor mutations that directly affect key regulators of cell death (such as BCL-2 family members). The development of novel techniques in the field of immunology and new animal models has greatly accelerated our understanding of oncogenic mechanisms in MYC-associated lymphomas. Mouse models are a powerful tool to reveal multiple genes implicated in the genesis of lymphoma and are extensively used to clarify the molecular mechanism of lymphoma, validating the gene function. Key features of MYC-induced apoptosis will be discussed here along with more recent studies on MYC direct and indirect interactors, including their cooperative action in lymphomagenesis. We review our current knowledge about the role of MYC-induced apoptosis in B-cell malignancies, discussing the transcriptional regulation network of MYC and regulatory feedback action of miRs during MYC-driven lymphomagenesis. More importantly, the finding of new modulators of apoptosis now enabling researchers to translate the discoveries that have been made in the laboratory into clinical practice to positively impact human health.

Highlights

The balance between cell survival and cell death represents an essential part of human tissue homeostasis, while altered apoptosis contributes to several pathologies and can affect the treatment efficacy
MYC is a family of transcription factors and consists of c-MYC, N-MYC, and L-MYC [1]
Development of novel techniques in the field of immunology and new animal models have greatly accelerated our understanding of oncogenic mechanisms in these MYC-associated lymphomas

Summary

Role of MYC in Non-Transformed Cells

MYC is a family of transcription factors and consists of c-MYC, N-MYC, and L-MYC (in this review, MYC will refer to c-MYC unless otherwise specified) [1]. Through its direct and indirect activity, MYC regulates the expression of several genes involved in cell proliferation, differentiation, metabolism, cell growth, and apoptosis [2]. MYC/MAX heterodimers bind the promoter of target genes through E-box motifs (CACGTG) to activate transcription [3]. The regulation of gene expression can involve multiple mechanisms including direct activation or inhibition of transcriptional machinery complex [4], induction of specific microRNAs [5], recruitment of chromatin remodeling complexes [6], mRNA stabilization and protein biogenesis [7]. MBIII–IV motifs of MYC are pivotal for the roles of MYC in apoptosis and in its protein turnover Another MYC key domain is represented by the bHLHZ motif that is required for the interaction between MYC and MAX, essential for DNA binding [14]. Because MYC is one of the most highly regulated proteins in the cell, many important regulatory mechanisms have been discovered through studies of MYC [17]

MYC and Lymphomagenesis

MYC Expression as a Key Factor of Apoptosis Activation

Crosstalk between MYC and Cellular Regulators of Apoptosis in Lymphoma

Regulatory Feedback Action of miRs during MYC-Driven Lymphomagenesis

Findings

Conclusions and Remarks