Abstract
c-MYC is one of the most essential transcriptional factors, regulating a diverse array of cellular functions, including proliferation, growth, and apoptosis. Dysregulation of c-MYC is essential in the pathogenesis of a number of B-cell lymphomas, but is rarely reported in T-cell lymphomas. c-MYC dysregulation induces lymphomagenesis by loss of the tight control of c-MYC expression, leading to overexpression of intact c-MYC protein, in contrast to the somatic mutations or fusion proteins seen in many other oncogenes. Dysregulation of c-MYC in B-cell lymphomas occurs either as a primary event in Burkitt lymphoma, or secondarily in aggressive lymphomas such as diffuse large B-cell lymphoma, plasmablastic lymphoma, mantle cell lymphoma, or double-hit lymphoma. Secondary c-MYC changes include gene translocation and gene amplification, occurring against a background of complex karyotype, and most often confer aggressive clinical behavior, as evidenced in the double-hit lymphomas. In low-grade B-cell lymphomas, acquisition of c-MYC rearrangement usually results in transformation into highly aggressive lymphomas, with some exceptions. In this review, we discuss the role that c-MYC plays in the pathogenesis of B-cell lymphomas, the molecular alterations that lead to c-MYC dysregulation, and their effect on prognosis and diagnosis in specific types of B-cell lymphoma.
Highlights
The proto-oncogene c-MYC, located at chromosome 8q24, is one of the genes most frequently involved in human carcinogenesis
This review summarizes the role of c-MYC in B-cell lymphomas and leukemias, in relation to the specific subtypes classified under the 2016 revision of the World Health
As BCL2 rearrangement is the one of the two “hits” in double-hit lymphoma, acquisition of c-MYC rearrangement during disease progression leads to histologic transformation to high-grade B-cell lymphoma/double-hit lymphomas (DHL) and rarely plasmablastic lymphoma or blastoid transformation of follicular lymphoma (FL)/B-lymphoblastic lymphoma [101,161,162]
Summary
The proto-oncogene c-MYC, located at chromosome 8q24, is one of the genes most frequently involved in human carcinogenesis. The transcription factor E2A immunoglobulin enhancer-binding factors (TCF3) is expressed in the GC dark zone B-cells and activates CCND3 and E2F2, which replace the CCND2-dependent proliferation in c-MYC+ GC B-cells [37]. C-MYC must be actively repressed in GC dark zone to limit the numbers of cell division before each round of antigen affinity-based selection [43], and allow normal affinity maturation to proceed, as c-MYC negatively regulates the transcriptional pause release of RNA polymerase II, which is essential for AID-mediated somatic hypermutation [44]. Abnormalities in AID activity at actively transcribed c-MYC gene locus can lead to translocations that juxtapose the Ig enhancer with the 5’ region of c-MYC, thereby abolishing the BCL6 mediated suppression of c-MYC expression in the GC dark zone [35]. The unregulated expression of c-MYC in GC B-cells leads to the bypass of affinity-based selection and perpetuation of the GC re-entry that significantly increases the chances of oncogenic genetic events for the development of B-cell lymphoma
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