Lenalidomide efficacy in activated B‐cell‐like subtype diffuse large B‐cell lymphoma is dependent upon IRF4 and cereblon expression

Abstract

SummaryDurable responses with lenalidomide monotherapy have been reported in patients with non-Hodgkin lymphoma. In relapsed/refractory diffuse large B-cell lymphoma (DLBCL), higher responses were observed in the activated B-cell-like (ABC) subtype than in the germinal centre B-cell-like subtype. Herein, the molecular mechanisms involved in the differential efficacy of lenalidomide in DLBCL subtypes were investigated. Using DLBCL cell lines, lenalidomide treatment was found to preferentially suppress proliferation of ABC-DLBCL cells in vitro and delay tumour growth in a human tumour xenograft model, with minimal effect on non-ABC-DLBCL cells. This tumouricidal effect was associated with downregulation of interferon regulatory factor 4 (IRF4), a hallmark of ABC-DLBCL cells. IRF4 inhibition by lenalidomide induced downregulation of B-cell receptor (BCR)-dependent NF-jB. Whereas IRF4-specific small, interfering RNA mimicked the effects of lenalidomide reducing NF-jB activation, IRF4 overexpression enhanced NF-jB activation and conferred resistance to lenalidomide. These findings indicate the crucial role of IRF4 inhibition in lenalidomide efficacy in ABC cells. Furthermore, lenalidomide-induced IRF4 downregulation required the expression of cereblon, a molecular target of lenalidomide. Taken together, these findings suggest that lenalidomide has direct antitumour activity against DLBCL cells, preferentially ABC-DLBCL cells, by blocking IRF4 expression and the BCR-NF-jB signalling pathway in a cereblon-dependent manner.

Lenalidomide in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: Is It a Valid Treatment Option?

“…This suggests that lenalidomide may be more effective when used as an early therapeutic option. Nevertheless, we confirmed that the advantage of lenalidomide treatment in non-GCB with respect to GCB is likely caused by the inhibitory activity of this immunomodulatory drug on the NF-kB pathway, which is aberrant in non-GCB [28]. In the present analysis, the drug dose (25 vs. 15 mg/day) significantly influenced the ORR, namely 51% vs. 21% (p 5 .002), mirroring the preclinical data on dosedependent pharmacokinetics [29].…”

EBV‐positive diffuse large B‐cell lymphoma of the elderly: 2016 update on diagnosis, risk‐stratification, and management

“…There were no differences in response rates, PFS and OS between the two groups. Lenalidomide can also target the ABC DLBCL by down regulating interferon regulatory factor (IRF4) and the NF-kB pathway [46]. Early clinical data showed preferential activity in refractory/relapsed ABC vs. GCB DLBCL, with an overall response rate (ORR) of 53% and 9%, respectively [47].…”

Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs

“…IMiDs are now known to be effective against not only multiple myeloma and 5q− syndrome, but also diffuse large B-cell lymphoma (DLBCL), a type of non-Hodgkin lymphoma, as well as mantle cell lymphoma, and these effects are known to also depend on CRBN [37,38]. In addition, the development of CC-122 (Fig.…”