Polymorphisms of the methylene tetrahydrofolate reductase and susceptibility to acute lymphoblastic leukemia in children

Background: Correlation between epigenetic factors and their effects on hematopoietic cells has led to a study of 2 common functional polymorphisms (C677T and A1298C) of 5,10-methylene tetrahydrofolate reductase (MTHFR) enzyme. The aim of this study was to assess the individual and/or combined roles of these 2 polymorphisms in pediatric acute lymphoblastic leukemia (ALL). Methods: Using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses, we studied the frequencies of the C677T and A1298C MTHFR genotypes in 103 pediatric ALL patients and 160 age-sex matched controls. We calculated the odds ratio (OR) of MTHFR genotypes to determine if 1 or both of these polymorphisms may be associated with childhood ALL. Results: The T allele frequency for MTHFR 677C>T was 22.2 and 18.45 in controls and cases, respectively. The C allele frequency for MTHFR 1298 A>C was 40.65 and 40.72 in controls and cases, respectively. The OR for MTHFR 677CT was 1.08 (95CI 0.58-1.95) and OR for MTHFR 677TT was 0.25 (95CI 0.05-10.24). The OR for MTHFR 1298 AC was 0.57 (0.95 CI 0.57-1.95) and for MTHFR CC was 0.96 (0.95 CI 0.37-2.45). The OR for the combined heterozygous status (677CT and 1298AC) was 1.08 (95 CI 0.41-2.82). Conclusion: Our findings suggest that the MTHFR C677T and A1298C gene variants lack a major influence on the susceptibility for pediatric ALL. Another result was that the C allele frequency for MTHFR 1298 A>C was significantly higher than those reported for most Asian and European populations. The C677T prevalence seems to be similar to those reported in most Asian populations. © 2011 by The American Society for Clinical Pathology

Detection of nucleophosmin and FMS-like tyrosine kinase-3 gene mutations in acute myeloid leukemia

BACKGROUND AND OBJECTIVES: Nucleophosmin gene mutations are frequently reported in acute myeloid leukemia (AML) patients with normal karyotype, which is also frequently associated with internal tandem duplication mutations in the FMS-like tyrosine kinase-3 gene. We sought to detect the nucleophosmin and FMS-like tyrosine kinase-3 (FLT3) internal tandem duplication (ITD) mutations among Iranian patients with AML and to assess the relationship between these mutations and the subtypes of the disease. DESIGN AND SETTING: Cross-sectional study of patients referred during 2007 through 2009. PATIENTS AND METHODS: Bone marrow and peripheral blood samples of 131 AML patients were randomly collected at the time of diagnosis and prior to treatment and the DNA extracted. After amplifying the nucleophosmin and FLT3 gene regions, positive cases were screened by conformation-sensitive gel electrophoresis and agarose gel electrophoresis techniques. RESULTS: Of 131 patients, 23 (17.5) (0.95 CI=0.107-0.244) had nucleophosmin gene mutations. The highest frequency of such mutations was found among the subtypes of M4 (30.4), M3 (21.7) and M5 (17.4). There was a high frequency of these mutations in the M3 subtype as well as a high frequency of allele D in all subtypes. Also, 21 (16.0) samples (0.95 CI=0.092-0.229) had FLT3/ITD mutation, of which 8 samples had mutant nucleophosmin (8 of 23, 35), and another 13 samples had wild-type nucleophosmin gene (13 of 108, 12). There was a high degree of association between the occurrence of nucleophosmin and FLT3/ITD mutations (P=.012). CONCLUSION: Our data showed a high frequency of NPM1 mutations in the monocytic subtypes of AML, as well as a high degree of association between the occurrence of NPM1 and FLT3/ITD mutations

Frequency of CYP1A1*2C polymorphism in patients with leukemia in the Iranian population

Background: CYP1A1, a member of the cytochrome P450 (CYP) enzymes, plays a very important role in metabolizing carcinogens. The aim of this case-control study was to detect the frequency of CYP1A1*2C polymorphism in Iranian leukemic patients and determine the role of this allele's variants, if any, as a risk factor for developing leukemia. Methods: Thirty-nine patients with chronic myeloid leukemia (CML), 105 with acute myeloid leukemia (AML), 95 healthy volunteers as the adult control group, 85 children with acute lymphoblastic leukemia (ALL), and 94 healthy children as the children control group were studied. Genomic DNA was assayed for restriction fragment length polymorphism (RFLP) in the CYP1A1*2C loci by amplification followed by digestion with BsrDI. Results: The frequencies of AA genotype (wild) were 82.05, 62.85, 84.70, 85.10, and 80 in CML, AML, ALL, the children control group, and the adult control group, respectively. The frequencies of AG genotype (heterogeneous) were 17.95, 36.20, 15.30, 14.90, and 18.95 in CML, AML, ALL, the children control group, and the adult control group, respectively. The frequencies of GG genotype (mutant) were 0.95 and 1.05 in AML and the adult control groups respectively; whereas, it was not observed in CML, ALL, or the children control group. Logistic regression analysis showed a significant correlation between the CYP1A1*2C polymorphism AG and AML patients (OR=2.4, 95 CI=1.3-4.7, P>0.05). Conclusion: A higher frequency of CYP1A1*2C, observed in AML patients, compared with the adult control group indicates an increased risk for AML in individuals carrying the heterozygote allele CYP1A1*2C. However, the results did not show any association between CYP1A1*2C genotypes and risk of ALL or CML. © 2011 by The American Society for Clinical Pathology

Fucoidan and cancer: A multifunctional molecule with anti-tumor potential

There is a wide variety of cancer types yet, all share some common cellular and molecular behaviors. Most of the chemotherapeutic agents used in cancer treatment are designed to target common deregulated mechanisms within cancer cells. Many healthy tissues are also affected by the cytotoxic effects of these chemical agents. Fucoidan, a natural component of brown seaweed, has anti-cancer activity against various cancer types by targeting key apoptotic molecules. It also has beneficial effects as it can protect against toxicity associated with chemotherapeutic agents and radiation. Thus the synergistic effect of fucoidan with current anti-cancer agents is of considerable interest. This review discusses the mechanisms by which fucoidan retards tumor development, eradicates tumor cells and synergizes with anti-cancer chemotherapeutic agents. Challenges to the development of fucoidan as an anti-cancer agent will also be discussed

Immunodeficiency, Centromeric Region Instability, and Facial Anomalies Syndrome (ICF) in a Boy with Variable Clinical and Immunological Presentations

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare primary immunodeficiency disorder characterized by recurrent infections and low immunoglobulin levels due to variable combined immunodeficiency, and centromeric region instability, and facial dysmorphism. We describe a 12-year-old boy with recurrent respiratory tract infections, facial anomalies, scoliosis, and psychomotor retardation. He had recurrent pneumonia with low serum IgG and IgM levels during infancy and preschool age. Later at the age of 10, he developed recurrent ear infections. An IgA and IgM deficiency was found accompanied by a normal B-cell and T-cell count as well as an impaired candida-induced T-cell proliferation. Further evaluations revealed a missense mutation in the DNMT3B gene on chromosome 20. Chromosomal analysis showed a sunburst multi-radial feature on chromosome 1, which is a hallmark of ICF syndrome. The genetic mutation and chromosomal abnormality along with clinical findings are compatible with the diagnosis of ICF syndrome. To the best of our knowledge, this is the first time that scoliosis is observed in an ICF patient. The additional variable clinical symptoms in the case were the presence of spastic gait as well as hypogammaglobulinemia with immunoglobulin isotype switch at different ages

LRRK2 inhibitors and their potential in the treatment of Parkinson’s disease: Current perspectives

� 2016 Atashrazm and Dzamko. Major advances in understanding how genetics underlies Parkinson’s disease (PD) have provided new opportunities for understanding disease pathogenesis and potential new targets for therapeutic intervention. One such target is leucine-rich repeat kinase 2 (LRRK2), an enigmatic enzyme implicated in both familial and idiopathic PD risk. Both academia and industry have promoted the development of potent and selective inhibitors of LRRK2, and these are currently being employed to assess the safety and efficacy of such compounds in preclinical models of PD. This review examines the evidence that LRRK2 kinase activity contributes to the pathogenesis of PD and outlines recent progress on inhibitor development and early results from preclinical safety and efficacy testing. This review also looks at some of the challenges remaining for translation of LRRK2 inhibitors to the clinic, if indeed this is ultimately warranted. As a disease with no current cure that is increasing in prevalence in line with an aging population, there is much need for developing new treatments for PD, and targeting LRRK2 is currently a promising option

Fucoidan Suppresses the Growth of Human Acute Promyelocytic Leukemia Cells In Vitro and In Vivo

Fucoidan, a natural component of seaweeds, is reported to have immunomodulatory and anti-tumor effects. The mechanisms underpinning these activities remain poorly understood. In this study, the cytotoxicity and anti-tumor activities of fucoidan were investigated in acute myeloid leukemia (AML) cells. The human AML cell lines NB4, KG1a, HL60, and K562 were treated with fucoidan and cell cycle, cell proliferation, and expression of apoptotic pathways molecules were analyzed. Fucoidan suppressed the proliferation and induced apoptosis through the intrinsic and extrinsic pathways in the acute promyelocytic leukemia (APL) cell lines NB4 and HL60, but not in KG1a and K562 cells. In NB4 cells, apoptosis was caspase-dependent as it was significantly attenuated by pre-treatment with a pan-caspase inhibitor. P21/WAF1/CIP1 was significantly up-regulated leading to cell cycle arrest. Fucoidan decreased the activation of ERK1/2 and down-regulated the activation of AKT through hypo-phosphorylation of Thr(308) residue but not Ser(473). In vivo, a xenograft model using the NB4 cells was employed. Mice were fed with fucoidan and tumor growth was measured following inoculation with NB4 cells. Subsequently, splenic natural killer (NK) cell cytotoxic activity was also examined. Oral doses of fucoidan significantly delayed tumor growth in the xenograft model and increased cytolytic activity of NK cells. Taken together, these data suggest that the selective inhibitory effect of fucoidan on APL cells and its protective effect against APL development in mice warrant further investigation of fucoidan as a useful agent in treatment of certain types of leukemia