Frequent Mutations in Natural Killer/T Cell Lymphoma

Zhang, Yanjie; Li, Chaoping; Xue, Weili; Zhang, Mingzhi; Li, Zhaoming

doi:10.1159/000492835

Cited by 36 publications

(32 citation statements)

References 81 publications

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“…TET2 truncating variants were detected in CLPD-NK (2/13) and ANKL (1/14) and different SET Domain containing epigenetic modifiers were mutated in both diseases (SETD1A and SETD1B in CLPD-NK, SETD2 in ANKL). DDX3X mutation, recurrent in ANKL 11 and in NKTCL 47 , was observed here for the first time in CLPD-NK. Other genes mutated both in CLPD-NK and ANKL patients included DDX11, RSF1, and KRAS.…”

Section: Discussionsupporting

confidence: 51%

A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells

et al. 2020

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The molecular pathogenesis of chronic lymphoproliferative disorder of natural killer (NK) cells (CLPD-NK) is poorly understood. Following the screening of 57 CLPD-NK patients, only five presented STAT3 mutations. WES profiling of 13 cases negative for STAT3/STAT5B mutations uncovered an average of 18 clonal, population rare and deleterious somatic variants per patient. The mutational landscape of CLPD-NK showed that most patients carry a heavy mutational burden, with major and subclonal deleterious mutations co-existing in the leukemic clone. Somatic mutations hit genes wired to cancer proliferation, survival, and migration pathways, in the first place Ras/MAPK, PI3K-AKT, in addition to JAK/STAT (PIK3R1 and PTK2). We confirmed variants with putative driver role of MAP10, MPZL1, RPS6KA1, SETD1B, TAOK2, TMEM127, and TNFRSF1A genes, and of genes linked to viral infections (DDX3X and RSF1) and DNA repair (PAXIP1). A truncating mutation of the epigenetic regulator TET2 and a variant likely abrogating PIK3R1negative regulatory activity were validated. This study significantly furthered the view of the genes and pathways involved in CLPD-NK, indicated similarities with aggressive diseases of NK cells and detected mutated genes targetable by approved drugs, being a step forward to personalized precision medicine for CLPD-NK patients.

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Section: Discussionsupporting

confidence: 51%

A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells

et al. 2020

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“…Deregulation of p53 in ENKTL may be attributed to mutations, EBNA1-induced p53 degradation and/or mutations in apoptotic proteins downstream of p53, such as FAS [66–68]. p53 mutations are present in up to 63% of cases of ENKTL by Sanger sequencing although they were detected at a lower frequency when assessed by next-generation sequencing [69]. The majority of mutations occur in the functional domain and were found to have a dominant negative function [69].…”

Section: Resisting Cell Deathmentioning

confidence: 99%

“…p53 mutations are present in up to 63% of cases of ENKTL by Sanger sequencing although they were detected at a lower frequency when assessed by next-generation sequencing [69]. The majority of mutations occur in the functional domain and were found to have a dominant negative function [69]. p53 mutations were also associated with advanced stage disease, suggesting this represents a secondary rather than an initiating oncogenic event in ENKTL [66, 70–72].…”

Section: Resisting Cell Deathmentioning

confidence: 99%

Molecular pathogenic pathways in extranodal NK/T cell lymphoma

et al. 2019

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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.

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“…MLL2 is an epigenetic regulator which plays a crucial role in cell development and metabolism [46]. Its function as a tumour suppressor has been described as well [47].…”

Section: Epigenetic Dysregulationmentioning

confidence: 99%

Pathogenesis and biomarkers of natural killer T cell lymphoma (NKTL)

et al. 2019

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Natural killer T cell lymphoma (NKTL) is an aggressive disease with very poor treatment outcomes in the advanced stages. With chemotherapy, initial response rates to treatment are high but responses are short lived. A better understanding of the complex molecular pathogenesis of this disease is essential in order to design and develop better therapeutics with improved efficacy. This review aims to summarise the key pathogenic mechanisms in NKTL which may have significant prognostic and therapeutic implications.

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Frequent Mutations in Natural Killer/T Cell Lymphoma

Cited by 36 publications

References 81 publications

A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells

A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells

Molecular pathogenic pathways in extranodal NK/T cell lymphoma

Pathogenesis and biomarkers of natural killer T cell lymphoma (NKTL)

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