Altered pathways and targeted therapy in double hit lymphoma

Abstract

High-grade B-cell lymphoma with translocations involving MYC and BCL2 or BCL6, usually referred to as double hit lymphoma (DHL), is an aggressive hematological malignance with distinct genetic features and poor clinical prognosis. Current standard chemoimmunotherapy fails to confer satisfying outcomes and few targeted therapeutics are available for the treatment against DHL. Recently, the delineating of the genetic landscape in tumors has provided insight into both biology and targeted therapies. Therefore, it is essential to understand the altered signaling pathways of DHL to develop treatment strategies with better clinical benefits. Herein, we summarized the genetic alterations in the two DHL subtypes (DHL-BCL2 and DHL-BCL6). We further elucidate their implications on cellular processes, including anti-apoptosis, epigenetic regulations, B-cell receptor signaling, and immune escape. Ongoing and potential therapeutic strategies and targeted drugs steered by these alterations were reviewed accordingly. Based on these findings, we also discuss the therapeutic vulnerabilities that coincide with these genetic changes. We believe that the understanding of the DHL studies will provide insight into this disease and capacitate the finding of more effective treatment strategies.

Generation of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance

“…These data confirm that we have established a model of aggressive B cell lymphoma, that has characteristics of human DHL, i.e. monoclonal, double high expression of c-MYC and BCL-2, cell surface expression of CD19, and a transcriptional profile distinct from other B cell tumours and consistent with aggressive human DHLs 21 , 37 . Our results suggest that both the BCL-2 inhibitor venetoclax and MCL-1 inhibitors (already in clinical trials for B cell malignancies but not DHL) 38 have potential for the treatment of this disease in humans, either as single agents or in combination.…”

“…Ep300, Stat6 ) that are observed in human DHL (Fig. 6b , Supplementary Table 2 and Supplementary Data 1 ) 37 .

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Identification of three small nucleolar RNAs (snoRNAs) as potential prognostic markers in diffuse large B‐cell lymphoma

“… 75 Currently, treatment strategies targeting the biosynthesis of MYC that affect tumor cells of DLBCL have been reported. 75 Drugs based on Rocaglates have been gradually applied in treatment of lymphomas with MYC mutations, with promising therapeutic value. 76 RPL10A belongs to the L1P family of ribosomal proteins.…”

“…Close links between MYC mutations and hematopoietic tumors are well‐known. Double‐hit DLBCL contains MYC translocations and translocations of BCL2 or BCL6 , with an extremely disappointing outcome, making MYC an attractive therapeutic target 75 . Currently, treatment strategies targeting the biosynthesis of MYC that affect tumor cells of DLBCL have been reported 75 .…”

“…Double‐hit DLBCL contains MYC translocations and translocations of BCL2 or BCL6 , with an extremely disappointing outcome, making MYC an attractive therapeutic target 75 . Currently, treatment strategies targeting the biosynthesis of MYC that affect tumor cells of DLBCL have been reported 75 . Drugs based on Rocaglates have been gradually applied in treatment of lymphomas with MYC mutations, with promising therapeutic value 76 .…”