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.

Keywords: Chemotherapy; Diffuse large B-cell lymphoma; Double hit lymphoma; Genetic alterations; Targeted therapy.

Fig. 1

Genetic and pathways alterations involved in DHL-BCL2

Fig. 2

Genetic and pathways alterations involved in DHL-BCL6. Note: *genes associated with the ubiquitin–proteasome system; #: the consequence of UBE2A mutation is not fully illustrated, might be functionally damaging [142]

Fig. 3

Structures of targeted agents in DHL-BCL2

Fig. 4

Structures of targeted agents in DHL-BCL6