Oncogenic pathways in distinct DLBCL subgroups

Comment on Tam et al, page 4090

In this issue of Blood, Tam and colleagues have detected mutations inactivating PRDM1/Blimp-1 in 8 of 35 diffuse large B-cell lymphomas (DLBCLs).

PRDM1/Blimp-1 has an important switch function orchestrating plasma-cell differentiation of B cells at the germinal center exit.¹  Its chromosomal site, 6q21, is often deleted in diffuse large B-cell lymphoma both of germinal center B-cell (GCB) and activated B-cell (ABC) type.²  According to Tam and colleagues, PRDM1/Blimp-1 occurs in the ABC-type, but not GCB-type DLBCL, as also detected in a parallel paper.³  This inactivation of PRDM-1 suggests that a disturbed terminal B-cell differentiation contributes to the pathogenesis of this type of DLBCL. It is based on the deletion of one allele and mutational inactivation of the other allele or on dominant-negative mutations, classical mechanisms of tumor suppressor gene inactivation.

PRDM1/Blimp-1 and BCL-6 mutually inhibit each other at the germinal center exit: BCL-6, expressed in the germinal center, represses PRDM1/Blimp-1, thereby sustaining the germinal center reaction and preventing plasma-cell differentiation. When the balance shifts in favor of Blimp-1, BCL-6 is down-regulated, proliferation ceases, and plasma-cell differentiation is induced.¹  Proliferation and differentiation thus occur as subsequent steps, at least in the germinal center reaction.

Imbalances in this double-negative feedback balance of BCL-6 and Blimp-1 have now been described for both molecules in DLBCL: BCL-6 may be overexpressed and dysregulated in DLBCL, supposedly of germinal center and post–germinal center differentiation,⁴  thereby preventing PRDM1/Blimp-1–driven differentiation. PRDM1/Blimp-1 inactivation, in contrast, may be functional in ABC-type, but not GCB-type, DLBCL, because its lack becomes manifest only when the molecule is physiologically up-regulated at the postfollicular differentiation stage. The degree of plasmacytic differentiation and function of genes downstream of PRDM1/Blimp-1 (such as the transcriptional activator XBP1) may indicate the degree of dysregulation and inactivation of this pathway. As a consequence, clear-cut secretory differentiation occurs in only a minority of ABC-type DLBCL.

Of interest, the mutual exclusion of proliferation (Ki-67 expression) and PRDM1/Blimp-1–driven differentiation holds true only at the germinal center exit. In the extrafollicular B-cell activation and reactivation of memory cells, proliferating Ki-67⁺ B cells simultaneously express Blimp-1 and differentiate into plasma cells, suggesting different regulatory mechanisms.⁵  Thus, the conceptual distinction of germinal-center exit versus memory-cell activation or extrafollicular B-cell activation (based on ongoing somatic hypermutations and immunoglobulin class switch) may allow a further correlation of their specific transformation mechanisms to their physiologic counterparts. ▪