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myc
The MYC proto-oncogene is located on chromosome 8q24 and encodes for a transcription factor with various roles in metabolism, protein synthesis, and cellular differentiation, among others. In the context of lymphoma, MYC expression leads to genomic instability, gene amplification, and cellular proliferation.8 MYC can also paradoxically lead to the repression of apoptosis by increasing the expression of the tumor suppressor TP53.9-11 To overcome this scenario, MYC requires the contribution of other genetic events (eg, the expression of BCL2 and mutations in TP53) to promote proliferation and oncogenesis.8 The spectrum of MYC effects appears dependent on the histologic context; for example, transcriptional targets in Burkitt lymphoma (BL) are completely distinct from transcriptional targets in DLBCL even though they share an identical t(8;14) rearrangement.12 In general, MYC rearrangements are strongly associated with increased proliferation.
Increased expression of the MYC protein can occur as a result of multiple mechanisms, including chromosomal translocations, MYC gene amplification, mutations within the gene, and copy number alterations.13, 14 Both the precise mechanism of MYC dysregulation and the presence of mutations within the MYC gene influence the level of MYC protein expression. The most frequently observed derangement leading to MYC protein overexpression involves the translocation of MYC to the immunoglobulin gene (IG) locus. Constitutive activity of the IG promoter results in a robust increase in messenger RNA levels and associated MYC protein expression. The MYC-IG rearrangement is the hallmark of BL and serves as a defining characteristic in approximately 60% of HGBL cases and in a minority of cases of DLBCL.1, 15-17 However, in approximately 5% of DLBCL cases, MYC rearrangements may involve a non-IG partner such as BCL6, BCL11A, or PAX5. In contrast to MYC-IG rearrangements, these aberrations generally lead to lower messenger RNA and MYC protein expression and may not portend as poor a prognosis.18-21 Finally, MYC gene amplification has been noted in approximately 2% to 20% of DLBCL cases, although the impact on the MYC protein expression levels and prognosis is unclear, with discordant findings in the literature.22-26