Molecular targets of glucocorticoids that elucidate their therapeutic efficacy in aggressive lymphomas

B cell receptor silencing reveals the origin of high-grade B cell lymphomas withMYCandBCL2rearrangements

“…Also, performing longitudinal IGK/LV gene tracking, we provide experimental proof for ongoing RAG-driven IG light chain editing in a primary HGBCL-DH-BCL2-BCL6 case extending analyses to the COH-THL1 cell line derivative (19) RAG-induced DNA breaks at cryptic RSS may also contribute to non-IG::MYC rearrangements in HGBCL-DH-BCL2, especially in a setting of impaired DNA repair (115). The expression of RAG1/2 in cell lines representative of BL and GCB-DLBCL predicts a broader contribution of the recombinases to the acquisition of structural variants and, more broadly to the fueling of genome instability in MYC-driven B cell lymphomas, supported by previous observations (116,117).…”

Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma

“…Due to the molecular heterogeneity and complex aberrant genetic landscape of DLBCL, we hypothesized that the inhibition of multiple driver pathways is necessary for the curative potential of targeted therapy. ViPOR synergistically targets key survival pathways in non-GCB DLBCL, including BCR-dependent NF-κB signaling using the combination of ibrutinib, lenalidomide, and prednisone, 21 , 22 , 23 , 27 as well as the anti-apoptotic protein BCL2 with venetoclax. In line with this hypothesis, ViPOR achieved a higher complete response rate (62%) and 2-year progression-free survival (39%) in non-GCB DLBCL than in GCB DLBCL, NOS.…”

“… 23 , 24 In the germinal center B-cell (GCB) subtype of DLBCL, cell viability is maintained by constitutive BCR-dependent PI3K signaling, BCL2, Ikaros, and Aiolos. 25 , 26 These survival pathways can be blocked by targeted drugs, including the BTK inhibitor ibrutinib, which targets BCR-dependent NF-κB activation, glucocorticoids, which target proximal BCR signaling, 27 the BCL2 inhibitor venetoclax, and lenalidomide, which targets Ikaros, Aiolos and, indirectly, IRF4. Preclinical studies have demonstrated synergistic killing of DLBCL cell lines by combinations of these drugs.…”