Constitutive Canonical NF-κB Activation Cooperates with Disruption of BLIMP1 in the Pathogenesis of Activated B Cell-like Diffuse Large Cell Lymphoma

Abstract

SUMMARY Diffuse large B-cell lymphoma (DLBCL) comprises disease entities with distinct genetic profiles, including germinal center B-cell (GCB) like and activated B-cell (ABC) like DLBCLs. Major differences between these two subtypes include genetic aberrations leading to constitutive NF-κB activation and interference with terminal B-cell differentiation through BLIMP1 inactivation, observed in ABC- but not GCB-DLBCL. Using conditional gain-of-function and/or loss-of-function mutagenesis in the mouse we show that constitutive activation of the canonical NF-κB pathway cooperates with disruption of BLIMP1 in the development of a lymphoma that resembles human ABC-DLBCL. Our work suggests that both NF-κB signaling, as an oncogenic event, and BLIMP1, as a tumor suppressor, play causal roles in the pathogenesis of ABC-DLBCL.

MicroRNA profiling of follicular lymphoma identifies microRNAs related to cell proliferation and tumor response

“…BLIMP1 mutations are frequently found in activated B cell (ABC)-like DLBCL, 45,46 and it has been demonstrated that BLIMP1 functions as a tumor suppressor. 46,47 Let-7a, miR-9, miR-125b have been shown to regulate BLIMP1 expression, 17,48,49 and miR-9 was reportedly increased in FL tissue samples and in germinal center B cells. 17,20 A similar pattern was observed in our study; we found that let-7a and miR-9 were over-expressed in FL tumor cells with down-regulation of BLIMP1.…”

IκB Kinase β (IKBKB) Mutations in Lymphomas That Constitutively Activate Canonical Nuclear Factor κB (NFκB) Signaling

“…It is already clear that dramatically increased numbers of marginal zone B cells in knock-in mice constitutively expressing IKK␤ (35) and phospho-mimetic activation loop IKK␤ knock-in mice cause lymphomagenesis (14). Although TALEN-or CRISPRbased mutagenesis has not yet been reported in genetic studies of cancer, we establish here that this is a powerful approach that can be employed in the study of tumorigenesis.…”

“…Serine 181 in the activation loop of IKK␤ is the crucial residue that needs to be phosphorylated by an upstream kinase for it to switch to its active conformation (13). A phospho-mimetic mutation in serine 181 can lead to constitutive activation of IKK␤, and constitutively activated IKK␤ can contribute to lymphoma generation in transgenic mice (14). Lysine 171, however, is situated parallel to serine 181 in the activation loop, and no structural models or experimental data exist to indicate whether the cancer-associated alterations found in this residue of IKK␤ activate or inactivate this critically important kinase, or if these changes represent functionally irrelevant "passenger" mutations.…”

Aspects moléculaires des lymphomes T périphériques (1)

“…Une inactivation de ce gène (mutations, délétions, répres-sions transcriptionnelles) est retrouvée chez 50 % des patients atteints de lymphome diffus à grandes cellules de type activé [78][79][80][81], et son rôle suppresseur de tumeur a été formellement montré dans ces lymphomes diffus en utilisant des modèles murins d'invalidation de PRDM1 [80,81]. Ce gène jouerait également un rôle important dans l'homéostasie T et la tolérance du soi [82,83].…”