Molecular mechanisms and pathogenetic role of BCL6 deregulation in diffuse large B-cell lymphomas — clinical and therapeutic implications

Abstract

BCL6 is the most frequently deregulated oncogene in diffuse large B-cell lymphoma (DLBCL),
the most common lymphoma in adults. BCL6 gene was first cloned from recurring
chromosomal translocations involving 3q27. BCL6 encodes a member of the BTB/POZ zinc
finger family of transcriptional repressors. Upon dimerization, BCL6 recruits distinct sets of
corepressors that mediate its biological activity. BCL6 expression in B-cells is required for
formation of germinal centers (GC). Within the GC, BCL6 controls the expression of multiple
genes that increase the tolerance to the physiological DNA breaks required for immunoglobulin
affinity maturation, regulate cell cycle progression, B-cell activation and differentiation.
Downregulation of BCL6 is required for B-cells to undergo further differentiation to memory
cells or plasma cells. Constitutive expression of BCL6 due to structural or functional
abnormalities in humans and mice inhibits B-cell differentiation and fosters acquisition of
additional lesions, leading to DLBCL. For these reasons, BCL6 represents a rational
therapeutic target in DLBCL with deregulated expression of this oncogene and reliant on its
continuous activity. Dissection of molecular structure-function relationships of the BCL6
protein allowed to design molecules specifically targeting this transcription factor and blocking
its function. Herein, we review recent advances in understanding the role of BCL6 in
lymphomagenesis and approaches to its therapeutic targeting.