Molecular pathogenic pathways in extranodal NK/T cell lymphoma

Abstract

Extranodal NK/T cell lymphoma, nasal type (ENKTL) is an aggressive malignancy with a dismal prognosis. Although l -asparaginase-based chemotherapy has resulted in improved response rates, relapse occurs in up to 50% of patients with disseminated disease. There is hence an urgent need for effective targeted therapy, especially for patients with relapsed or refractory disease. Novel insights gleaned from high-throughput molecular and genomic profiling studies in recent years have contributed significantly to the understanding of the molecular biology of ENKTL, which exemplifies many of the hallmarks of cancer. Deregulated pro-proliferative signaling pathways, such as the Janus-associated kinase/signal transducer and activator of transcription (JAK/STAT), platelet-derived growth factor (PDGF), Aurora kinase, MYC, and NF-κB, have been identified as potential therapeutic targets. The discovery of the non-canonical function of EZH2 as a pro-proliferative transcriptional co-activator has shed further light on the pathogenesis of ENKTL. Loss of key tumor suppressor genes located on chromosome 6q21 also plays an important role. The best-studied examples include PR domain zinc finger protein 1(PRDM1), protein tyrosine phosphatase kappa (PTPRK), and FOXO3. Promoter hypermethylation has been shown to result in the downregulation of other tumor suppressor genes in ENKTL, which may be potentially targeted through hypomethylating agents. Deregulation of apoptosis through p53 mutations and upregulation of the anti-apoptotic protein, survivin, may provide a further growth advantage to this tumor. A deranged DNA damage response as a result of the aberration of ataxia telangiectasia-related (ATR) kinases can lead to significant genomic instability and may contribute to chemoresistance of ENKTL. Recently, immune evasion has emerged as a critical pathway for survival in ENKTL and may be a consequence of HLA dysregulation or STAT3-driven upregulation of programmed cell death ligand 1 (PD-L1). Immunotherapy via inhibition of programmed cell death 1 (PD-1)/PD-L1 checkpoint signaling holds great promise as a novel therapeutic option. In this review, we present an overview of the key molecular and pathogenic pathways in ENKTL, organized using the framework of the “hallmarks of cancer” as described by Hanahan and Weinberg, with a focus on those with the greatest translational potential.

HKDC1 C-terminal based peptides inhibit extranodal natural killer/T-cell lymphoma by modulation of mitochondrial function and EBV suppression

“…ENKTL is involved in multiple pathogenic pathways, such as JAK/STAT, PDGF, Aurora kinase, NFκB, and the c-Myc pathway, making it difficult to identify potential molecular targeting therapies for ENKTL [8]. ENKTL is characterized by EBV latent infection with the expression of EBNA1 and LMP1, and specific inhibitors for these viral proteins have been found to suppress EBV-dependent tumor growth in xenograft models.…”

“…However, ENKTL still relapses eventually [13], indicating that these methods cannot interrupt the potential original driving force that was triggered by EBV DNA. This makes EBV DNA a novel potential therapeutic target in ENKTL treatment [8,14].…”

Multifaceted Role of PRDM Proteins in Human Cancer

“…Then, it appeared as a pleiotropic regulatory factor participating at the B lymphocyte terminal differentiation [14]. PRDM1/BLIMP1 is also expressed in T and NK (natural killer) cells where it regulates their homeostasis [15][16][17]. The human gene is localized on chromosome 6q21-q22.1, a locus frequently deleted in lymphoid tumors.…”

“…The human gene is localized on chromosome 6q21-q22.1, a locus frequently deleted in lymphoid tumors. It encodes for a transcription repressor and it is a well-established tumor suppressor gene in human DLBCL (diffuse large B cell lymphoma) and in other hematological malignancies [17,18]. Initially, in 2006, structural alterations inactivating PRDM1/BLIMP1 were identified in DLBCLs in two independent studies [19,20].…”

“…Recent high-throughput molecular and genomic profiling analyses have significantly contributed to the understanding of the molecular basis of T and NK cell lymphomas. For instance, array comparative genomic hybridization and gene expression profiling in extranodal NK/T-cell lymphoma (EN-NK/T) revealed that the most frequently deleted chromosomal region 6q21-6q25, induced a downregulation of several tumor-suppressor genes including PRDM1 [17,30]. Once again, its inactivation might be also due to PRDM1 gene mutation, aberrant miRNA upregulation, and/or other epigenetic changes such as hypermethylation [31,32].…”