Molecular Pathogenesis of Diffuse Large B-Cell Lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL) is divided into germinal center B-like (GCB) DLBCL and activated B-like (ABC) DLBCL. In recent years, whole genome sequencing (WGS), whole exome sequencing (WES), and transcriptome sequencing (RNA-seq) have been performed for samples from many patients with DLBCL. Here, I present a review of the results of next generation sequencing data for DLBCL. Somatic mutations show a low identity between studies with only 10-20% gene overlap. DLBCL is a disease that results from various molecular pathogeneses. Mutations in genes involved in chromatin remodeling were found in the GCB subtype. Mutations in members of B-cell receptor (BCR) signaling and the NF-κB pathway (MYD88) were found in the ABC subtype. The MYD88 L265P mutation was observed in 29% of ABC DLBCL cases. EZH2 mutations were observed in 21.7% of GCB DLBCL cases. WGS indicated that inactivating mutations in GNA13 (Gα protein) were prevalent in GCB DLBCL cases. In addition, S1PR2 is a target of aberrant somatic hypermutation. In recent years, samples from patients with relapsed and refractory DLBCL were analyzed. The activation of the NF-κB pathway is associated with treatment resistance in DLBCL. Further clarification of the molecular pathogenesis of DLBCL is expected to lead to the development of individualized treatment for the disease.

Retracted: GNA13 promotes tumor growth and angiogenesis by upregulating CXC chemokines via the NF‐κB signaling pathway in colorectal cancer cells

“…6 Among them, the G12 protein comprises Gα12 (GNA12) and Gα13 (GNA13) and plays a critical role in promoting cancer cell growth and oncogenic transformation. 7,8 Previous studies have implicated that GNA12 proteins crucially regulate dorsal ruffle turnover, which is involved in an incredible array of functions, including tumor cell invasion, micropinocytosis, metastasis, and others. 9,10 However, there are more studies that have focused on the role of GNA12 in cancer biology, but few have studied the specific role of GNA13.…”

Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses

“…11). Mutations in the genes involved in the NF-κB pathway induce ABC-DLBCL 44 . Furthermore, polymorphisms in HOIP are a risk factor for ABC-DLBCL 23 .…”

“…HOIPINs induce cell death in B cell lymphoma cell lines. In diffuse large B cell lymphoma (DLBCL), activated B cell-like DLBCL (ABC-DLBCL) is reportedly induced by constitutively elevated NF-κB activation, whereas the germinal center B cell-like DLBCL (GCB-DLBCL) is associated with defects in chromatin remodeling 44,45 . Importantly, the polymorphisms in HOIP are closely associated with ABC-DLBCL 23 .…”

Epigenetic inhibitors sensitize DLBCL cells to rituximab and doxorubicin

“…The most striking result was the identification of a missense mutation on gene EZH2 in the GCB cell line Su-Dhl-4, showing the highest response to EZH2-inhibitor tazemetostat. This EZH2 inhibitor has the highest efficacy in EZH2 -mutated DLBCL patients belonging to the GCB subtype ( 45 ), and the mutation found in Su-Dhl-4 cells has been reported as a potential biomarker for response to EZH2 inhibitors ( 46 ). Moreover, tazemetostat treatment significantly deregulated the expression of cell cycle genes in this cell line, potentially causing cell cycle arrest, a mechanism suggested by Knutson et al (43 ).…”