Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis and classification

Abstract

MYC is a potent oncogene initially identified as the target of the t(8;14)(q24;q32) chromosome translocation in Burkitt lymphoma. MYC gene alterations have been identified in other mature B-cell neoplasms that are usually associated with an aggressive clinical behavior. Most of these tumors originate in cells that do not normally express MYC protein. The oncogenic events leading to MYC up-regulation seem to overcome the inhibitory effect of physiological repressors such as BCL6 or BLIMP1.Aggressive lymphomas frequently carry additional oncogenic alterations that cooperate with MYC dysregulation, likely counteracting its proapoptotic function. The development of FISH probes and new reliable antibodies have facilitated the study of MYC gene alterations and protein expression in large series of patients, providing new clinical and biological perspectives regarding MYC dysregulation in aggressive lymphomas. MYC gene alterations in large B-cell lymphomas are frequently associated with BCL2 or BCL6 translocations conferring a very aggressive behavior. Conversely, MYC protein up-regulation may occur in tumors without apparent gene alterations, and its association with BCL2 overexpression also confers a poor prognosis. In this review, we integrate all of this new information and discuss perspectives, challenges, and open questions for the diagnosis and management of patients with MYC-driven aggressive B-cell lymphomas. (Blood. 2013;122(24):3884-3891) Introduction MYC was initially identified as the target oncogene dysregulated by the t(8;14)(q24;q32) translocation in Burkitt lymphoma (BL). MYC rearrangements involving the heavy-and light-chain immunoglobulin (IGL) loci and different non-IG genes were subsequently detected in other lymphoid neoplasms usually associated with very aggressive clinical behavior.1,2 The transforming oncogenic potential of MYC was initially demonstrated in cell lines and transgenic animal models. However, MYC dysregulation alone does not cause lymphoma, 4 and the t(8;14) has been found at very low levels in blood and BM of healthy individuals, 5 indicating that this genetic alteration per se is not sufficient to trigger lymphomagenesis. BL and most lymphomas carrying MYC translocations are among the most proliferative tumors. However, MYC expression has been difficult to identify in the germinal center (GC), the lymphoid cell compartment with the highest proliferative fraction, where most of these tumors originate. Understanding the possible role of MYC in normal lymphoid regulation and particularly the modulation of the GC reaction has been elusive.Recent studies, including basic immunology analyses, new animal models, next-generation sequencing, and clinicopathological observations, are converging to provide a new perspective of the role of MYC in the lymphoid system and the pathogenesis of aggressive lymphomas. In this review, we integrate all of this new information and discuss new perspectives, challenges, and open questions for the diagnosis and management of patients. MYC as a transc...

Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers

“…Activating genetic alterations of MYC, including genomic rearrangements, copy number gains, or amplifications, are common driving events in certain cancers. For example, acquisition of MYC alterations and subsequent upregulation of MYC and MYC target genes have been implicated as key events in the transformation of indolent follicular lymphoma (FL) to highly aggressive diffuse large B-cell lymphoma (DLBCL) and is also observed in de novo DLBCL (2,3). Alternatively, other oncogenic events drive cancer by inducing epigenetic changes that promote MYC overexpression such as in NUT midline carcinoma (NMC), a poorly differentiated, highly aggressive subtype of squamous cell carcinoma that primarily arises in midline organs (4).…”

Scoring of MYC protein expression in diffuse large B-cell lymphomas: concordance rate among hematopathologists

“…1 Subsequently, MYC gene alterations have been discovered in B-cell neoplasms other than Burkitt lymphoma. 2 Among those neoplasms, diffuse large B-cell lymphoma is the most widely studied. The presence of MYC rearrangements in patients with diffuse large B-cell lymphoma treated with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP) has been shown to be associated with poor prognosis.…”

MYC as therapeutic target in leukemia and lymphoma

“…Overall, MYC gene rearrangements constitute the third most common aberrancy in this type of lymphoma (6%-15% of cases) and confer a bad prognosis. 42,45 They are usually secondary events that appear in the context of complex karyotypes and are more frequently detected in DLBCL with a germinal center B-cell (GCB) phenotype. 45,46 B-cell lymphoma unclassifiable (BCLU) with features intermediate between DLBCL and BL is a provisional entity described in the latest version of the WHO classification to designate those cases that share both clinical and biological characteristics between DLBCL and the BL, but that cannot be clearly assigned to any of those categories.…”

“…41 Approximately 60% of these mutations result in increased stability of the protein via reduced ubiquitin-mediated proteolysis. [41][42][43] Additional transforming mechanisms have been described to contribute to the pathogenesis of the different subtypes of BL. EBV genome is detected in all endemic patients and has been shown to cooperate with MYC in the pathogenesis of this subtype.…”