The Role of c-MYC in B-Cell Lymphomas: Diagnostic and Molecular Aspects

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.

Keywords: c-MYC; complex karyotype; diffuse large B-cell lymphoma; double-hit lymphoma; lymphoma; mantle cell lymphoma; plasmablastic lymphoma.

Figure 1

A typical case of double-hit lymphoma (DHL). (A) Hematoxylin and eosin (H&E) section shows sheets of medium-sized lymphoid cells with blastoid chromatin and mitotic figures. The lymphoma cells are positive for B-cell marker cluster differentiation 20 (CD20) (B); germinal center marker (cluster differentiation 10 (CD10) (C); B-cell lymphoma protein 2 (BCL2) (D); and c-MYC (F); and show a high proliferation rate by Ki-67 (>90%) (E).

Figure 2

(A) Karyotype of DHL with c-MYC/IGL and BCL2/IGH rearrangements. Clonal evolution related triplication of the derivative (18) t(14;18) highlights the complex additional alterations; (B) fluorescent in-situ hybridization (FISH) targeting c-MYC using a flanking break-apart probe set. Fusion (arrow) represents the normal locus. The separated red and green signals indicate c-MYC rearrangement; (C) Dual fusion FISH targeting immunoglobin heave chain (IGH) (green) and BCL2 (red). One fusion signal represents derivative 14 and the remaining three fusions signals are the oncogenic 18 derivatives (arrows). Absence of a normal 18 (an isolated red signal) agrees with the karyotype and is likely due to mitotic recombination-based evolution, transferring the fusion site to the original normal homolog, in addition to the more common nondisjunction-based duplication for the third derivative in this etiology.