Liucheng Rong

Methylenetetrahydrofolate reductase polymorphisms, serum methylenetetrahydrofolate reductase levels, and risk of childhood acute lymphoblastic leukemia in a Chinese population

(Cancer Sci 2010; 101: 782–786)

LncRNA NALT interaction with NOTCH1 promoted cell proliferation in pediatric T cell acute lymphoblastic leukemia.

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 MIF −173G/C polymorphism and risk of childhood acute lymphoblastic leukemia in a Chinese population

Migration inhibitory factor (MIF) has recently been defined as a novel pro-tumorigenic factor that promotes cell proliferation, migration, and invasion. The MIF -173C allele results in increased MIF promoter activity and is associated with a higher serum MIF level. We hypothesized that this polymorphism may contribute to childhood acute lymphoblastic leukemia (ALL) susceptibility. We genotyped the MIF -173G/C polymorphism (rs755622) in 346 ALL cases and 516 cancer-free controls in a Chinese population and found that the variant genotype GC and the combined genotypes GC/CC were associated with a significantly higher risk of childhood ALL [adjusted odds ratio (OR)=1.39, 95% confidence interval (CI)=1.01-1.93 for GC and adjusted OR=1.38, 95% CI=1.01-1.89 for GC/CC]. In addition, we found that the increased risk was more pronounced among high-risk ALL and B-phenotype ALL patients. Our results suggest that the MIF -173G/C polymorphism is involved in the etiology of childhood ALL and is a potential candidate gene for determining cancer susceptibility. Further validations in other populations are warranted.

Association of genetic variations in mTOR with risk of childhood acute lymphoblastic leukemia in a Chinese population

Abstract 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.

hOGG1 Ser326Cys polymorphism and risk of childhood acute lymphoblastic leukemia in a Chinese population

Oxidative DNA damage caused by reactive oxygen species can produce 8‐oxoguanine (8‐oxoG) in DNA, which is misread and leads to G:C→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 B‐phenotype 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)

Impact of age on the survival of pediatric leukemia: an analysis of 15083 children in the SEER database

BACKGROUND & AIMS Age 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. METHODS In 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. RESULTS There 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. CONCLUSIONS Age at diagnosis remained to be a crucial determinant of the survival variability of pediatric leukemia patients.

Function of SLC7A7 in T-Cell Acute Lymphoblastic Leukemia

Background/Aims: Y+LAT1 protein, encoded by the SLC7A7 gene (a member of the SLC7 family), forms the cationic amino acid transport system y+L (system y+L). This system transports cationic amino acids such as arginine and lysine out of the cell. Arginine, in particular, is critical for T-cell activation and function in the immune response. Methods: We analyzed the role of the SLC7A7 gene in the cellular activities of Jurkat cells, specifically the cell cycle and cell proliferation, apoptosis, migration, and invasion. Cell proliferation was assessed using the Cell Counting Kit-8. Apoptosis and the cell cycle were determined with a FACSCalibur flow cytometer. A Transwell chamber was used to measure cell invasion and migration. Results: The proliferative ability of Jurkat cells was not significantly altered by transfection with SLC7A7 overexpression vectors. However, SLC7A7 overexpression significantly decreased the percentage of apoptotic Jurkat cells (P = 0.007) but significantly increased the proportion of G1 phase cells (P = 0.029) and cell migration (P < 0.001) and invasion (P < 0.001). Knockdown of SLC7A7 increased the cell apoptosis rate (P = 0.006) but decreased the G1 phase ratio (P = 0.002) and cell migration (P < 0.001) and invasion (P < 0.001). Conclusions: SLC7A7 plays a significant role in the pathogenesis of T-cell acute lymphoblastic leukemia.

Bone marrow infiltrated Lnc-INSR induced suppressive immune microenvironment in pediatric acute lymphoblastic leukemia

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.

Interleukin-2 and Interleukin-8 Gene Polymorphisms and Acquired Aplastic Anemia Risk in a Chinese Population

Background/Aims: Cytokines IL-2 and IL-8 both participate in immune regulation. However, the relationship between polymorphisms in these two cytokines and the risk of acquired aplastic anemia (acquired AA) has not been explored. Methods: We selected five SNPs including rs11575812, rs2069772 and rs2069762 of IL-2, rs2227306 and rs2227543 of IL-8. SNaPshot genotyping was used to test the genotypes of IL-2 and IL-8 polymorphisms in a population of 101 acquired AA patients and 165 healthy controls. Results: The rs2069762 G allele appeared to be a protective mutation, but no significant differences were found in other four SNPs. We also found that rs2069762 had an impact on the transcriptional regulation. Conclusions: It could be assumed that the rs2069762 polymorphism might reduce the risk of acquired aplastic anemia, while the remaining four SNPs might not contribute to susceptibility to acquired AA in a Chinese population.