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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aggressive NK-cell leukemia (ANKL) is a rare form of NK cell neoplasm that is more prevalent among people from Asia and Central and South America. Patients usually die within days to months, even after receiving prompt therapeutic management. Here we performed the first comprehensive study of ANKL by integrating whole genome, transcriptome and targeted sequencing, cytokine array as well as functional assays. Mutations in the JAK-STAT pathway were identified in 48% (14/29) of ANKL patients, while the extracellular STAT3 stimulator IL10 was elevated by an average of 56-fold (P < 0.0001) in the plasma of all patients examined. Additional frequently mutated genes included TP53 (34%), TET2 (28%), CREBBP (21%) and MLL2 (21%). Patient NK leukemia cells showed prominent activation of STAT3 phosphorylation, MYC expression and transcriptional activities in multiple metabolic pathways. Functionally, STAT3 activation and MYC expression were critical for the proliferation and survival of ANKL cells. STAT signaling regulated the MYC transcription program, and both STAT signaling and MYC transcription were required to maintain the activation of nucleotide synthesis and glycolysis. Collectively, the JAK-STAT pathway represents a major target for genomic alterations and IL10 stimulation in ANKL. This newly discovered JAK/STAT-MYC-biosynthesis axis may provide opportunities for the development of novel therapeutic strategies in treating this subtype of leukemia.
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PMID:Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia. 2914 41

Epstein-Barr virus (EBV), which is associated with B-cell proliferative disorders, also transforms T- or natural killer (NK)-lineage cells and has been connected with various T- or NK (T/NK)-cell malignancies, such as extranodal NK/T-cell lymphoma-nasal type and aggressive NK-cell leukemia. Chronic active EBV (CAEBV) disease , which occurs most often in children and young adults in East Asia, is an EBV-associated T-/NK-cell lymphoproliferative disease. Patients with CAEBV often progress to overt lymphoma or leukemia over a long-term clinical course. EBV's transforming capacity in B cells is well characterized, but the molecular pathogenesis of clonal expansion caused by EBV in T/NK cells has not yet been clarified. In the primary infection, EBV infects B cells and epithelial cells and may also infect some T/NK cells. In some individuals, because of poor presentation by specific human leukocyte antigens or the genetic background, EBV-infected T/NK cells evade host immunity and survive. Occasionally, with the help of viral oncogenes, EBV-associated T/NK lymphoproliferative diseases, such as CAEBV, may develop. The subsequent accumulation of genetic mutations and/or epigenetic modifications in driver genes, such as DDX3X and TP53, may lead to overt lymphoma and leukemia. Activation-induced cytidine deaminase and the APOBEC3 family, driven by EBV infection, may induce chromosomal recombination and somatic mutations.
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PMID:EBV in T-/NK-Cell Tumorigenesis. 2989 80

Epstein Barr virus positive T/NK lymphoproliferative disorders (EBV-TNKLPD) comprise a spectrum of neoplasms ranging from cutaneous lymphoid proliferations to aggressive lymphomas. The spectrum includes extranodal NK/T-cell lymphoma (ENKTL), aggressive NK-cell leukemia, and a group of EBV-TNKLPDs affecting children which are poorly characterized in terms of their molecular biology. Gene and miRNA expression profiling has elucidated RNA abnormalities which impact on disease biology, classification, and treatment of EBV-TNKLPD. Pathways promoting proliferation, such as Janus associated kinase/ Signal Transducer and Activator of Transcription (JAK/STAT) and nuclear factor kB, are upregulated in ENKTL while upregulation of survivin and deregulation of p53 inhibit apoptosis in both ENKTL and chronic active EBV infection (CAEBV). Importantly, immune evasion via the programmed cell death-1 and its ligand, PD-1/PD-L1 checkpoint pathway, has been demonstrated to play an important role in ENKTL. Other pathogenic mechanisms involve EBV genes, microRNA deregulation, and a variety of other oncogenic signaling pathways. The identification of EBV-positive Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) as a tumor with a distinct molecular signature and clinical characteristics highlights the important contribution of the knowledge derived from gene and miRNA expression profiling in disease classification. Novel therapeutic targets identified through the study of RNA abnormalities provide hope for patients with EBV-TNKLPD, which often has a poor prognosis. Immune checkpoint inhibition and JAK inhibition in particular have shown promise and are being evaluated in clinical trials. In this review, we provide an overview of the key transcriptomic aberrancies in EBV-TNKLPD and discuss their translational potential.
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PMID:Transcriptomic Abnormalities in Epstein Barr Virus Associated T/NK Lymphoproliferative Disorders. 3070 77

EBV-negative aggressive NK-cell leukemia/lymphoma (ANKL) is a recently recognized, rare NK-cell neoplasm that preferentially affects non-Asians and has a fulminant clinical course. Little is known about the genetic alterations of this disease. In this study, we performed comprehensive molecular genetic studies, including chromosomal analysis, fluorescence in situ hybridization, single nucleotide polymorphism (SNP) microarray, and next-generation sequencing (NGS), on 4 patients diagnosed in our institution. The results demonstrated that our EBV-negative ANKLs have highly complex genomic profiles characterized by near-triploid/near-tetraploid karyotype (3 of 3) with numerous structural abnormalities, inactivation of TP53 (3 of 3), overexpression of c-Myc (4 of 4), strong expression of PD-L1 in neoplastic cells (2 of 4), and gain of the 11q23-ter region (2 of 2). Our study provides important insights of EBV-negative ANKL, which share many of the genetic features with their EBV-positive counterpart. The strong expression of Programmed death-ligand 1 (PD-L1) suggests that immune checkpoint inhibitors may be further explored as a potential therapeutic option for this highly aggressive, chemotherapy-resistant NK-cell neoplasm.
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PMID:Comprehensive molecular genetic studies of Epstein-Barr virus-negative aggressive Natural killer-cell leukemia/lymphoma. 3289 Jun 1