Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin's lymphoma. A total of 10%‒15% of DLBCL cases are associated with myelocytomatosis viral oncogene homolog(MYC) and/or B-cell lymphoma-2 (BCL2) translocation or amplification. BCL2 inhibitors have potent anti-tumor effects in DLBCL; however, resistance can be acquired through up-regulation of alternative anti-apoptotic proteins. The histone deacetylase (HDAC) inhibitor chidamide can induce BIM expression, leading to apoptosis of lymphoma cells with good efficacy in refractory recurrent DLBCL. In this study, the synergistic mechanism of chidamide and venetoclax in DLBCL was determined through in vitro and in vivo models. We found that combination therapy significantly reduced the protein levels of MYC, TP53, and BCL2 in activated apoptotic-related pathways in DLBCL cells by increasing BIM levels and inducing cell apoptosis. Moreover, combination therapy regulated expression of multiple transcriptomes in DLBCL cells, involving apoptosis, cell cycle, phosphorylation, and other biological processes, and significantly inhibited tumor growth in DLBCL-bearing xenograft mice. Taken together, these findings verify the in vivo therapeutic potential of chidamide and venetoclax combination therapy in DLBCL, warranting pre-clinical trials for patients with DLBCL.
Aminopyridines ; Animals ; Benzamides ; Biological Phenomena ; Bridged Bicyclo Compounds, Heterocyclic ; Down-Regulation ; Histone Deacetylase Inhibitors/therapeutic use* ; Humans ; Lymphoma, Large B-Cell, Diffuse/pathology* ; Mice ; Neoplasm Recurrence, Local ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Proto-Oncogene Proteins c-myc/therapeutic use* ; Sulfonamides ; Tumor Suppressor Protein p53/metabolism*

Myc and p53 proteins are closely associated with many physiological cellular functions, including immune response and lymphocyte survival, and are expressed in the lymphoid organs, which are sites for the development and activation of B-cell malignancies. Genetic alterations and other mechanisms resulting in constitutive activation, rearrangement, or mutation of MYC and TP53 contribute to the development of lymphomas, progression and therapy resistance by gene dysregulation, activation of downstream anti-apoptotic pathways, and unfavorable microenvironment interactions. The cross-talk between the Myc and p53 proteins contributes to the inferior prognosis in many types of B-cell lymphomas. In this review, we present the physiological roles of Myc and p53 proteins, and recent advances in understanding the pathological roles of Myc, p53, and their cross-talk in lymphoid neoplasms. In addition, we highlight clinical trials of novel agents that directly or indirectly inhibit Myc and/or p53 protein functions and their signaling pathways. Although, to date, these trials have failed to overcome drug resistance, the new results have highlighted the clinical efficiency of targeting diverse mechanisms of action with the goal of optimizing novel therapeutic op-portunities to eradicate lymphoma cells.

Myc and p53 proteins are closely associated with many physiological cellular functions, including immune response and lymphocyte survival, and are expressed in the lymphoid organs, which are sites for the development and activation of B-cell malignancies. Genetic alterations and other mechanisms resulting in constitutive activation, rearrangement, or mutation of MYC and TP53 contribute to the development of lymphomas, progression and therapy resistance by gene dysregulation, activation of downstream anti-apoptotic pathways, and unfavorable microenvironment interactions. The cross-talk between the Myc and p53 proteins contributes to the inferior prognosis in many types of B-cell lymphomas. In this review, we present the physiological roles of Myc and p53 proteins, and recent advances in understanding the pathological roles of Myc, p53, and their cross-talk in lymphoid neoplasms. In addition, we highlight clinical trials of novel agents that directly or indirectly inhibit Myc and/or p53 protein functions and their signaling pathways. Although, to date, these trials have failed to overcome drug resistance, the new results have highlighted the clinical efficiency of targeting diverse mechanisms of action with the goal of optimizing novel therapeutic op-portunities to eradicate lymphoma cells.

Accumulating evidence confirmed that many dysregulated signaling pathways and aberrant genetic alterations contribute to the oncogenesis and heterogeneity of lymphoid malignancies. Therapeutically targeting dysregulating signaling pathways and their hidden oncogenic biomarkers are becoming available, but did not show desired therapeutic effect in current clinical practice. It is meaningful to further understand the underlying mechanisms of the dysregulated signaling pathways and to address the potential utility of pathway-related biomarkers. To precisely identify the dysregulation of signaling pathways and the "driver" oncogenic biomarkers, as well as to develop reliable and reproducible risk-stratification based on biomarkers will be challenging. Never-theless, pathway-based targeted therapy will raise the hope to improve the outcomes of the patients with lymphoid malignancies, especially with aggressive types, and the efficient utility of pathway-related biomarkers in diagnosis, prognosis, prediction of lymphoid malignancies may also be able to power precision medicine.

Accumulating evidence confirmed that many dysregulated signaling pathways and aberrant genetic alterations contribute to the oncogenesis and heterogeneity of lymphoid malignancies. Therapeutically targeting dysregulating signaling pathways and their hidden oncogenic biomarkers are becoming available, but did not show desired therapeutic effect in current clinical practice. It is meaningful to further understand the underlying mechanisms of the dysregulated signaling pathways and to address the potential utility of pathway-related biomarkers. To precisely identify the dysregulation of signaling pathways and the "driver" oncogenic biomarkers, as well as to develop reliable and reproducible risk-stratification based on biomarkers will be challenging. Never-theless, pathway-based targeted therapy will raise the hope to improve the outcomes of the patients with lymphoid malignancies, especially with aggressive types, and the efficient utility of pathway-related biomarkers in diagnosis, prognosis, prediction of lymphoid malignancies may also be able to power precision medicine.

Epstein-Barr virus, a ubiquitous human herpesvirus, can induce both lytic and latent infections that result in a variety of human diseases, including lymphoproliferative disorders. The oncogenic potential of Epstein-Barr virus is related to its ability to infect and transform B lymphocytes into continuously proliferating lymphoblastoid cells. However, Epstein-Barr virus has also been implicated in the development of T/natural killer cell lymphoproliferative diseases. Epstein-Barr virus encodes a series of products that mimic several growth, transcription and anti-apoptotic factors, thus usurping control of pathways that regulate diverse homeostatic cellular functions and the microenvironment. However, the exact mechanism by which Epstein-Barr virus promotes oncogenesis and inflammatory lesion development remains unclear. Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases often have overlapping clinical symptoms as well as histologic and immunophenotypic features because both lymphoid cell types derive from a common precursor. Accurate classification of Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases is a prerequisite for appropriate clinical management. Currently, the treatment of most T/natural killer cell lymphoproliferative diseases is less than satisfactory. Novel and targeted therapies are strongly required to satisfy clinical demands. This review describes our current knowledge of the genetics, oncogenesis, biology, diagnosis and treatment of Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases.
Cell Transformation, Viral ; Epstein-Barr Virus Infections/*complications ; Herpesvirus 4, Human/*physiology ; Humans ; Killer Cells, Natural/immunology/metabolism/*pathology/*virology ; Lymphoproliferative Disorders/diagnosis/*etiology/therapy ; T-Lymphocytes/immunology/metabolism/*pathology/*virology

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, affecting >90% of the adult population. EBV targets B-lymphocytes and achieves latent infection in a circular episomal form. Different latency patterns are recognized based on latent gene expression pattern. Latent membrane protein-1 (LMP-1) mimics CD40 and, when self-aggregated, provides a proliferation signal via activating the nuclear factor-kappa B, Janus kinase/signal transducer and activator of transcription, phosphoinositide 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase pathways to promote cellular proliferation. LMP-1 also induces BCL-2 to escape from apoptosis and gives a signal for cell cycle progression by enhancing cyclin-dependent kinase 2 and phosphorylation of retinoblastoma (Rb) protein and by inhibiting p16 and p27. LMP-2A blocks the surface immunoglobulin-mediated lytic cycle reactivation. It also activates the Ras/PI3K/Akt pathway and induces Bcl-xL expression to promote B-cell survival. Recent studies have shown that ebv-microRNAs can provide extra signals for cellular proliferation, cell cycle progression and anti-apoptosis. EBV is well known for association with various types of B-lymphocyte, T-lymphocyte, epithelial cell and mesenchymal cell neoplasms. B-cell lymphoproliferative disorders encompass a broad spectrum of diseases, from benign to malignant. Here we review our current understanding of EBV-induced lymphomagenesis and focus on biology, diagnosis and management of EBV-associated B-cell lymphoproliferative disorders.
B-Lymphocytes/*pathology/*virology ; Diagnosis, Differential ; Disease Management ; Epstein-Barr Virus Infections/*complications ; Herpesvirus 4, Human/*physiology ; Humans ; Lymphoproliferative Disorders/*diagnosis/*etiology/therapy