Epstein-Barr virus (EBV) initially isolated from cultured Burkitt lymphoma (BL) cells, is

No abstract

RUNX3, runt-domain transcription factor, is a master regulator of gene expression in major developmental pathways. It acts as a tumor suppressor in many cancers but is oncogenic in certain tumors. We observed upregulation of RUNX3 mRNA and protein expression in nasal-type extranodal natural killer (NK)/T-cell lymphoma (NKTL) patient samples and NKTL cell lines compared to normal NK cells. RUNX3 silenced NKTL cells showed increased apoptosis and reduced cell proliferation. Potential binding sites for MYC were identified in the RUNX3 enhancer region. Chromatin immunoprecipitation–quantitative PCR revealed binding activity between MYC and RUNX3. Co-transfection of the MYC expression vector with RUNX3 enhancer reporter plasmid resulted in activation of RUNX3 enhancer indicating that MYC positively regulates RUNX3 transcription in NKTL cell lines. Treatment with a small-molecule MYC inhibitor (JQ1) caused significant downregulation of MYC and RUNX3, leading to apoptosis in NKTL cells. The growth inhibition resulting from depletion of MYC by JQ1 was rescued by ectopic MYC expression. In summary, our study identified RUNX3 overexpression in NKTL with functional oncogenic properties. We further delineate that MYC may be an important upstream driver of RUNX3 upregulation and since MYC is upregulated in NKTL, further study on the employment of MYC inhibition as a therapeutic strategy is warranted.

Recently we reported the different frequencies of p53 and c-kit gene mutations among sinonasal NK/T cell lymphoma (NKTCL) in Korea, north China (Beijing), and Japan, suggesting some racial, environmental, or life-style differences as a possible cause of nasal tumorigenesis. In this study, gene mutations in p53, c-kit, Kras, and β β β β-catenin gene were analyzed by polymerase chain reaction (

No abstract

Epstein-Barr virus (EBV) initially isolated from the cultured Burkitt lymphoma (BL) cells, is one of the wellknown oncogenic virus. The NAB-2 line, which was established from a North American Burkitt's tumor, was indicated to contain one copy of EBV DNA as the integrated form into chromosome 2p13 of the host genome. To demonstrate the integration site of EBV directly, and to clarify the relation between the integration sites and the oncogenes, fragments containing the nucleotide sequence of NAB-2 integration sites were cloned. EBV was integrated via the terminal repeats (TR), and integration sites located in the clone RP11-440P5 on chromosome 2, between two oncogenes, REL and BCL11A, which is apart from approximately 350 kbp from each other. Expression level of REL in NAB-2 was increased. The flanking region of chromosome 2 at the bilateral junction sites showed no homology to the junction sites of EBV. The integration site 2p13 overlaps with common fragile site, FRA2E. NAB-2 cells expressed almost all latent genes but LMP-2A that flanks the TR, indicating the type III of latent infection of EBV. Integration event in NAB-2 might alter the regulation of the oncogenes and provide advantage for continuous cell proliferation.

Mutations of DNA double-strand breaks (DSB) repair genes, ATM, MRE11, RAD50, NBS1 and ATR, are postulated to play a role in the development of gastrointestinal malignancies with an impaired mismatch repair (MMR) function. In the present study, mutations of these genes together with the presence of microsatellite instability (MSI) were examined in 50 leukemia-lymphoma cell lines. MSI was detected in 13 (26%) lines. Mutations of intronic mononucleotide repeats in ATM and MRE11 were found in nine and six lines, respectively, whereas mutations of mononucleotide repeats of RAD50 were found in only one line, and none were found in either NBS1 or ATR. Frequencies of ATM and MRE11 mutations were significantly higher in MSI-positive than MSInegative lines. These mutations generated aberrant splicing in both genes. The intensity of the aberrant transcript of ATM E xposure to hazardous agents in the environment may induce DNA damage that could be harmful to the maintenance of cell homeostasis and transmission of highfidelity genetic information. Thus, cells have evolved several mechanisms for DNA repair to ensure genomic integrity and prevent mutations. The DNA MMR system corrects errors that might occur during DNA replication, whereas HR and non-homologous end joining are involved in the repair of DNA DSB.(1,2) Double-strand breaks, which are extremely cytotoxic DNA lesions, activate an extensive array of responses that lead to repair of the damage and allow continuation of cellular life.(1,3) The nuclear protein kinase ATM is regarded as the primary activator of this network, phosphorylating key proteins in numerous signaling pathways.(4) The highly conserved MRN complex plays a role in DSB repair, particularly in the HR pathways.(5) While NBS1 is a target of ATM, recent observation has shown that the MRN complex itself contributes to the direct activation of ATM.(6) ATR, another protein kinase, has been reported to regulate responses to a broad range of damage, including DSB. (7,8) Whereas ATM is engaged primarily in DSB repair, several observations suggest that ATR has a critical role in virtually all cellular responses to the arrest of DNA replication forks, which are the DNA structures formed during replication. (8)(9)(10) The increased rate of uncorrected replication errors at simple repeat sequences is known as MSI. Disruption of the MMR system, as revealed by MSI, is characterized by the accelerated accumulation of single nucleotide mutations and resultant alterations in the microsatellite DNA sequences, which affect the genome ubiquitously.(11) MSI is correlated with hereditary non-polyposis colorectal cancer, as well as a variety of sporadic cancers, including gastric, endometrial and colorectal cancers, through inactivation of several MMR target genes. (12,13) Although MSI was previously regarded to be uncommon in hematolymphoid malignancies, (14,15) recent studies have revealed it to be involved in the development of these malignancies, especially diseases involving the T-cell lineage. (16,17) Recent studies h...

The validity of CDT as a diagnostic tool is still questionable. If the higher values for sensitivity that some studies report can be confirmed by others it is a useful diagnostic tool in unselected populations. However, more methodologically sound, comparable studies need to be performed before firm conclusions can be drawn.