Long non-coding RNA (lncRNA) was referred to be participating in various malignant tumors. Location based analysis of the mechanism in lncRNA and genes have been highly focused. In this study, we reported that lncRNA named NALT which was located near NOTCH1 within 100 bp away. We confirmed that up-regulation of NALT associating with NOTCH1 in human samples. Increased expression of NALT dramatically promoted cell proliferation in cell lines via CCK8 assay and EDU stain. Further xenograft tumor also indicated the growth inducing affection of NALT while could be partial reversed by GSI. Besides, through sorting the side-population cells in T ALL cells treated with NALT shRNA could decrease percentage of SP cell which companied by the down-regulation of NOTCH1. Gal4-λN/BoxB reporter system revealed that the nuclear located NALT could function as a transcription activator which caused an activation of NOTCH signal pathway as confirmed by western blot. Taken together, we found a neighbor of NOTCH1, Lnc-RP11-611D20.2 (named NALT) which could regulate the NOTCH1 signal pathway through cis-regulation. This founding may trigger a comparable development of diagnosis or novel molecularly-directed therapies.

The mammalian target of rapamycin (mTOR) is an important protein kinase regulating cell survival and apoptosis. To determine whether genetic variations in mTOR are associated with risk of acute lymphoblastic leukemia (ALL) in Chinese children, we genotyped two tag single nucleotide poymorphisms (SNPs) in mTOR (rs2536 and rs2295080) in a case-control study. We observed that the variant genotype TC of mTOR rs2536 was associated with a significantly decreased risk of childhood ALL (adjusted odds ratio [OR] = 0.67, 95% confidence interval [CI] = 0.46-0.96), and the association was more pronounced in high-risk ALL and T-phenotype ALL groups. Additionally, we found that the combined genotypes TC/CC decreased the risk of ALL only in the high-risk ALL group (adjusted OR = 0.54, 95% CI = 0.32-0.91) and T-phenotype ALL group (adjusted OR = 0.29, 95% CI = 0.10-0.84). These results suggest that the mTOR rs2536 polymorphism is involved in the susceptibility to childhood ALL in a Chinese population.

No abstract

Immune escape due to immunosuppressive microenvironments, such as those associated with regulatory T (Treg) cells is highly associated with initial occurrence and development of solid tumors or hematologic malignancies. Here, we employed high-throughput transcriptome screening to demonstrate immunosuppression-associated increases in the long noncoding (lnc) RNA lnc-insulin receptor precursor (INSR), which was corrected with INSR expression in CD4+ T cells extracted from the bone marrow of patients with childhood acute T lymphoblastic leukemia. Loss-of-function and gain-of-function assays in vitro and in vivo revealed that membrane-localized and cytoplasm-localized lnc-INSR promoted Treg distribution and decreased the percentage of cytotoxic T lymphocytes, which induced tumor growth. Through direct binding with INSR, lnc-INSR blocked the INSR ubiquitination site, causing abnormal activation of INSR and the phosphatidylinositide 3-kinase/AKT-signaling pathway. These results indicated that lnc-INSR might promote immune suppression by enhancing Treg-cell differentiation and serve as valuable therapeutic targets in the immunosuppressive tumor microenvironment.

Methylenetetrahydrofolate reductase (MTHFR), involved in DNA methylation and nucleotide synthesis, is thought to be associated with a decreased risk of adult and childhood acute lymphoblastic leukemia (ALL). Accumulating evidence has indicated that two common genetic variants, C677T and A1298C, are associated with cancer risk. We hypothesized that these two variants were associated with childhood ALL susceptibility and influence serum MTHFR levels. We genotyped these two polymorphisms and detected MTHFR levels in a case-control study of 361 cases and 508 controls. Compared with the 677CC and 677CC ⁄ CT genotypes, the 677TT genotype was associated with a statistically significantly decreased risk of childhood ALL (odds ratio = 0.53, 95% confidence interval = 0.32-0.88, and odds ratio = 0.55, 95% confidence interval = 0.35-0.88, respectively). In addition, a pronounced reduced risk of ALL was observed among low-risk ALL and B-phenotype ALL. Moreover, the mean serum MTHFR level was 8.01 ng ⁄ mL (±4.38) in cases and 9.27 ng ⁄ mL (±4.80) in controls (P < 0.001). MTHFR levels in subjects with 677TT genotype was significantly higher than those with 677CC genotype (P = 0.010) or 677CT genotype (P = 0.043) in controls. In conclusion, our results provide evidence that the MTHFR polymorphisms might contribute to reduced childhood ALL risk in this population. (Cancer Sci 2010; 101: 782-786) A cute lymphoblastic leukemia (ALL) is the most common acute leukemia in children, (1) representing approximately one-third of all pediatric cancers. Approximately 30 new cases per one million people are diagnosed every year, with a peak incidence in patients aged 2-5 years in the USA. (2) To date, the mechanisms that underlie the occurrence of ALL remain largely unknown. Mutations in several genes, together with dietary effects, environmental exposure to carcinogens, and individual immune systems are suggested to be the risk factors that predispose individuals to develop ALL. (3,4) Folate is one of the most important coenzymes in DNA synthesis, and methylenetetrahydrofolate reductase (MTHFR) is the crucial enzyme in folate metabolism. MTHFR can cause methylation of homocysteine into methionine, leading to methylation of DNA. (5) MTHFR C677T (rs1801133) and A1298C (rs1801131) are the two common polymorphisms in the MTHFR gene. Studies have revealed that MTHFR C677T is associated with reduced enzyme activity, thermolability, and mild to moderate hyperhomocysteinemia, especially during times of folate insufficiency. (6,7) MTHFR A1298C is associated with lower enzymatic activity but does not seem to influence homocysteine plasma levels, except when accompanied by C677T variation. (8,9) Previous studies have shown that individuals with homozygous 677TT would have a reduced incidence of colorectal cancer (10,11) and leukemia. (12) However, the associations between the MTHFR polymorphisms and risk of ALL remained conflicting. (13,14) In the present study, we explored the role of these two MTHFR polymorphisms in childhood ALL patients in a C...

Background/Aims: IGF1 is a key regulator in cell proliferation and apoptosis, and the 3' un-translated region (3'UTR) of the gene plays an important role in gene expression. For the first time, we explored the relationship between polymorphisms in the IGF1 3'UTR region and the risk of childhood acute lymphoblastic leukemia (ALL). Methods: Questionnaires were applied to collect epidemiological data. The genotypes of IGF1 polymorphisms were tested in a population of 744 ALL patients and 1088 cancer-free controls utilizing Taqman. Cell functional studies included real-time PCR, cell culture and transfection and luciferase assays. Results: We found that rs6214 homozygous AA genotype and rs6218 homozygous CC genotype were significantly associated with increased risk of childhood ALL. In addition, rs6218 CC genotype was associated with increased level of IGF1 mRNA in bone marrow, and the mutation in rs6218 led to aberrant binding capacity of hsa-miR-603 and hsa-miR-3941 in the 3'UTR of IGF1. Conclusion: Polymorphisms of rs6214 and rs6218 in the 3'UTR of IGF1 are associated with childhood ALL susceptibility, and the polymorphism of rs6218 is related with IGF1 expression at mRNA level.

Oxidative DNA damage caused by reactive oxygen species can produce 8-oxoguanine (8-oxoG) in DNA, which is misread and leads to G:C fi T:A transversions. This can be carcinogenic. Repair of 8-oxoG by the base excision repair pathway involves the activity of human 8-oxoG DNA glycosylase 1 (hOGG1). Accumulating evidence suggests that the hOGG1 Ser326Cys polymorphism affects the activity of hOGG1 and might serve as a genetic marker for susceptibility to several cancers. To determine whether this polymorphism is associated with risk of childhood acute lymphoblastic leukemia (ALL) in Chinese children, we genotyped the hOGG1 Ser326Cys polymorphism (rs1052133) in a case-control study including 415 cases and 511 controls. We found that there was a significant difference in the genotype distributions of the hOGG1 Ser326Cys polymorphism between cases and controls (P = 0.046), and the combined genotypes Ser/Ser and Ser/Cys were associated with a statistically significantly decreased risk of ALL (adjusted odds ratio [OR] = 0.66, 95% confidence interval [CI] = 0.49-0.88, P = 0.005). Furthermore, we found a decreased risk for high risk ALL (adjusted OR = 0.60, 95% CI = 0.40-0.88, P = 0.005), low risk ALL (adjusted OR = 0.68, 95% CI = 0.47-0.99, P = 0.042), and Bphenotype ALL (adjusted OR = 0.63, 95% CI = 0.46-0.86, P = 0.003) among children with the Ser/Ser and Ser/Cys genotypes. Our results suggest that the hOGG1 Ser326Cys polymorphism is associated with susceptibility to childhood ALL in a Chinese population. (Cancer Sci 2011; 102: 1123-1127 A cute lymphoblastic leukemia (ALL) is a clonal disease of a lymphoblast and is the most frequent malignancy in children younger than 15 years, accounting for approximately 25% of all pediatric malignancies.(1) Studies of developed countries report that cancer incidence among children has risen steadily since the 1950s, with 38 new cases per million occurring every year.(2) Like other cancers, childhood ALL is generally believed to be caused by a combination of genetic susceptibility factors and environmental exposures. DNA damage to hematopoietic precursor cells is essential for the development of leukemia, (4,5) which occurs at an estimated rate of 10 000 lesions per cell per day.(6) Correspondingly, several DNA repair pathways have evolved to maintain the genetic integrity of cells and prevent carcinogenesis, including base excision repair (BER), (7)(8)(9) mismatch repair, and nucleotide excision repair. The DNA lesion 8-oxoguanine (8-oxoG), produced by reactive oxygen species, is one of the most common forms of oxidative damage to DNA, and leads to G:C fi T:A transversions, causing carcinogenesis.(10,11) Human 8-oxoG DNA glycosylase 1 (hOGG1) is a key enzyme in the BER pathway and repairs 8-oxoG. (7,12) Many functional and epidemiological studies have suggested that the Ser326Cys polymorphism in exon 7 of the hOGG1 gene might affect the activity of the enzyme, (13,14) and therefore may serve as a genetic marker for susceptibility to various cancers. (15)(16)(17)(18) Additionally, a r...

BACKGROUND & AIMSAge at diagnosis is a key factor for predicting the prognosis of pediatric leukemia especially regarding the survivorship assessment. In this study, we aimed to assess the impact of this prognostic factor such as age in children with pediatric leukemia.METHODSIn this study, Surveillance, Epidemiology, and End Results Program-registered children with leukemia during 1988-2013 were analyzed. All patients were divided into five groups according to the age at the time of diagnosis (<1, 1-4, 5-9, 10-15, >15 years old). Kaplan-Meier and multivariable Cox regression models were used to evaluate leukemia survival outcomes and risk factors.RESULTSThere was significant variability in pediatric leukemia survival by age at diagnosis including ALL, AML and CML subtypes. According to the survival curves in each group, survival rate were peaked among children diagnosed at 1–4 years and steadily declined among those diagnosed at older ages in children with ALL. Infants (<1 year) had the lowest survivorship in children with either ALL or AML. However, children (1-4 years) harbored the worst prognosis suffering from CML. A stratified analysis of the effect of age at diagnosis was validated as independent predictors for the prognosis of pediatric leukemia.CONCLUSIONSAge at diagnosis remained to be a crucial determinant of the survival variability of pediatric leukemia patients.