MYC-driven aggressive B-cell lymphomas: biology, entity, differential diagnosis and clinical management

Abstract

MYC, a potent oncogene located at chromosome locus 8q24.21, was identified initially by its involvement in Burkitt lymphoma with t(8;14)(q24;q32). MYC encodes a helix-loop-helix transcription factor that accentuates many cellular functions including proliferation, growth and apoptosis. MYC alterations also have been identified in other mature B-cell neoplasms and are associated with aggressive clinical behavior. There are several regulatory factors and dysregulated signaling that lead to MYC up-regulation in B-cell lymphomas. One typical example is the failure of physiological repressors such as Bcl6 or BLIMP1 to suppress MYC over-expression. In addition, MYC alterations are often developed concurrently with other genetic alterations that counteract the proapoptotic function of MYC. In this review, we discuss the physiologic function of MYC and the role that MYC likely plays in the pathogenesis of B-cell lymphomas. We also summarize the role MYC plays in the diagnosis, prognostication and various strategies to detect MYC rearrangement and expression.

A Circulating microRNA Signature Predicts Age-Based Development of Lymphoma

“…The miRNA signature network for Smurf2 T/T mice versus wild type, revealed MYC and JUN as key targets (Fig 6A & 6B). Both MYC and JUN are known to play an important role in DLBCL development and progression [7, 47–49]. The impact on MYC and JUN from this circulating miRNA signature on the entire host starting at 3 months of age likely act as a trigger for eventual development of DLBCL.…”

“…This miRNA signature was further modulated at older ages associated with the beginning of DLBCL tumor formation. When determining the impact of the miRNA signature on DLBCL biology, it was discovered that these miRNAs had the most prominent impact on genes, MYC [48, 49] and JUN [7, 47], with global impact on cancer related functions starting at age several months before actual DLBCL formation. We have previously shown that JUN is a key driver for DLBCL with aging [8].…”

Glucose Metabolism Reprogrammed by Overexpression of IKKϵ Promotes Pancreatic Tumor Growth

“…This is very significant, as c-MYC is frequently deregulated not only in PDAC, but several other cancers as well (44, 45). c-MYC is shown to integrate cellular metabolism with survival and proliferation of cancer cells through the regulation of a number of genes (46).…”

Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

“…Recently, studies have posited a 'c-Myc function rule,' in which c-Myc is a 'universal amplifier' of active (expressed) genes in lymphocytes. 33,34,57 In summary, both MYC rearrangement and Myc overexpression have advantage and limitations as a single biomarker in DLBCL, and their prognostic importance is significantly different in GCB-vs ABC-DLBCL. GCB subtype (opposite to the general association of ABC-DLBCL with poorer survival) of MYC-R + DLBCL with Myc overexpression was associated with significantly poorer survival, likely contributed by significantly higher Myc protein levels as well as associated tumor biology.…”

“…Our results suggest that fluorescence in situ hybridization analysis for MYC rearrangements and immunohistochemistry evaluation for Myc and Bcl-2 expression are both needed to determine the prognosis in subsets of patients. 57 Insights gained into the tumor biology associated with MYC abnormalities are important for understanding the functional role of MYC in lymphomagenesis and chemoresistance, Occurrence of GCB vs ABC subtype of MYC-R + /Myc high /Bcl-2 high : 2.5 Prognosis of GCB vs ABC subtype of MYC-R + : trends towards poorer OS and PFS (P = 0.11); Prognosis of GCB vs ABC subtype of MYC-R + /Myc high : no significant difference (slightly unfavorable trends); Prognosis of GCB vs ABC subtype of MYC-R + /Myc high /Bcl-2 high : unfavorable trends (for PFS, P = 0.098) Abbreviations: ABC, activated-B-cell like; Bcl-2 high , high Bcl-2 protein expression; DLBCL, diffuse large B-cell lymphoma; DPL, double-positive lymphoma; EFS, event-free survival; GCB, germinal center B-cell like; Myc high , high Myc protein expression; Myc low , low Myc protein expression; MYC-R + , MYC rearrangement positive; MYC-R¯, MYC rearrangement negative; OS, overall survival; PFS, progression-free survival. Note: Case numbers marked by * are the total Myc high or Myc low case numbers (with or without MYC-R status determined).…”