Dysregulation of Cell Survival in Diffuse Large B Cell Lymphoma: Mechanisms and Therapeutic Targets

Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common type of lymphoma worldwide, representing 30-40% of non-Hodgkin lymphomas, and is clinically aggressive. Although more than half of patients with DLBCL are cured by using standard first-line immunochemotherapy, the remaining patients are refractory to the first-line therapy or relapse after complete remission and these patients require novel therapeutic approaches. Understanding the pathogenesis of DLBCL is essential for identifying therapeutic targets to tackle this disease. Cell survival dysregulation, a hallmark of cancer, is a characteristic feature of DLBCL. Intrinsic signaling aberrations, tumor microenvironment dysfunction, and viral factors can all contribute to the cell survival dysregulation in DLBCL. In recent years, several novel drugs that target abnormal cell survival pathways, have been developed and tested in clinical trials of patients with DLBCL. In this review, we discuss cell survival dysregulation, the underlying mechanisms, and how to target abnormal cell survival therapeutically in DLBCL patients.

Keywords: BCL2; BCR signaling; DLBCL; EBV; TME; apoptosis; cell survival; p53.

Figure 1

Regulation of B cell receptor (BCR) signaling on B cell survival. Antigen dependent BCR signaling engages several downstream pathways, which include the NF-κB pathway, PI3K/AKT/mTOR pathway, NFAT pathway, and MAPK/ERK pathway. NF-κB activation promotes transcription of the pro-survival genes including BCL2, BFL1, cellular inhibitor of apoptosis protein (cIAP) 1, cIAP2, X-linked inhibitor of apoptosis protein (XIAP) and so on. Additionally, NF-κB antagonizes the function of p53, thereby decreasing p53-mediated cell apoptosis. Activated AKT phosphorylates forkhead box class O family member transcription factors (FOXOs), suppressing the transcription of target genes including pro-apoptosis gene BIM. AKT activation also results in the activation of pro-survival MCL1. Moreover, AKT mediates the phosphorylation of the pro-apoptotic BCL2 family member BAD, and blocks BAD-induced cell apoptosis. The activation of mTOR complex 1 (mTORC1), which suppresses BAD, could be induced by AKT activation or CARD11 activation. Tonic BCR signaling triggers activation of the PI3K/AKT pathway and also promotes cell survival. BTK, Bruton tyrosine kinase; DAG, diacylglycerol; IP3, inositol trisphosphate; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PKCβ, protein kinase C β; PLCλ2, phospholipase λ2; SYK, spleen tyrosine kinase.

Figure 2

Genetic aberrations causing p53 dysfunction leads to dysregulated cell survival. Mutations involving the coding DNA sequence region of the TP53 gene affect the protein structure and abrogate p53 tumor suppressor function. Other aberrations lead to decreased p53 translation or stability or altered protein modification. MDM2 and MDM4 also inhibit p53-mediated transcription activation. Decreased p53 nuclear accumulation caused by MDM2 amplifications or KDM6B deletions leads to p53 dysfunction. Impaired p53 function leads to decreased transcription of pro-apoptotic genes, resulting in abnormally enhanced cell survival.

Figure 3

Survival signals from the tumor microenvironment. Immune cells and stromal cells promote tumor cell survival through cell-to-cell contact and secreting pro-survival factors. Several types of cells in the tumor microenvironment secret pro-survival factors including B-cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), hedgehog (Hh) ligands, and interleukin-10 (IL-10). These factors bind to corresponding receptors on the tumor cell surface, providing important pro-survival signals to the tumor cells. Neutrophils form neutrophil extracellular traps (NETs), which activate Toll-like receptor 9 (TLR9) pathway to promote survival of diffuse large B cell tumor cells. CXCL8, C-X-C motif chemokine ligand 8; IL-8, interleukin-8.

Figure 4

Epstein-Barr virus (EBV) contributes to dysregulation of survival of diffuse large B cell lymphoma (DLBCL) cells. In EBV positive DLBCL, LMP1, EBV nuclear antigen 2 (EBNA2), and several EBV microRNAs could lead to abnormal survival of DLBCL cells, contributing to the pathogenesis of EBV positive DLBCL. These factors lead to enhanced survival of DLBCL cells by increasing pro-survival signals or suppressing pro-apoptotic proteins. Abbreviations: BART, Bam HI A region rightward transcript; CTAR, C-terminal activation region; TRADD, tumor necrosis factor receptor type 1–associated death domain; TRAF, tumor necrosis factor receptor associated factor.