6DMAP inhibition of early cell cycle events and induction of mitotic abnormalities

N-6 dimethylaminopurine (6DMAP) has been shown to induce aberrant mitosis in different cell types including Chinese hamster fibroblasts (CHEF/18), The mechanism of action and the cellular targets, however, are still not clear, We showed previously that in CHEF/18 cells this compound inhibits DNA synthesis with a kinetic of inhibition suggestive of an effect on early events of the cell cycle, In this paper we investigated which cellular targets were affected by 6DMAP and found that: (i) the compound inhibits phosphorylation of ribosomal protein S6 and activation of the 70 kDa S6 kinase (p70(S6k)) known to be activated by epidermal growth factor (EGF) in keeping with the notion that it is a protein kinase inhibitor; however the inhibition in vivo appears to be specific as MAP kinase phosphorylation is not inhibited; (ii) 6DMAP drastically affects cytoskeletal components leading to a rapid morphological change in most cells. These data, together with the findings that the dose range and the treatment time effective in inducing the micronuclei containing chromosomes were the same as for DNA synthesis inhibition, suggest that a disturbance in G(1) of signal transduction pathways may contribute to abnormal mitosis

Are genotypes of glutathione S-transferase superfamily a risk factor for childhood acute lymphoblastic leukemia? Results of an Italian case-control study.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer accounting for approximately 25\u201330% of all childhood malignancies. Despite much investigation, the causes of the disease are not yet fully understood. Like many other cancers, ALL is considered to be a complex disease determined by a combination of genetic and environmental factors

Analysis of Telomeres in Peripheral Blood Cells From Patients With Bone Marrow Failure

BACKGROUND: The determination of telomere length is useful for the characterization of dyskeratosis congenita (DC) and of aplastic anemias (AA) as well as hematological malignancies. Short telomeres result from a specific defect of telomere maintenance in DC and likely from higher cellular turnover in AA and hematological malignancies. Data are not conclusive for Diamond-Blackfan anemia (DBA), a pure erythroid aplasia due to defects of ribosomal proteins. Our aim was to evaluate the utility of a qPCR method for telomere length assessment to evaluate the diagnostic contribution of telomere measurement in bone marrow failure syndromes (BMFS). PROCEDURE: Telomere length was evaluated by qPCR in peripheral blood cells from 95 normal individuals and 62 patients with BMFS, including 45 patients with DBA. RESULTS: Results obtained with qPCR are comparable with other quantitative methods, such as flow-FISH and Southern blotting. Our data show that only one DBA patient and a minority of other BMFS patients have very short telomeres, defined as less than the 1st percentile of controls. CONCLUSIONS: The qPCR method for telomere length evaluation is an easy alternative to other methods and may thus be valuable in a clinical hematological laboratory setting. Telomere maintenance does not seem to be involved in the pathogenesis of DBA unlike in other BMFSs

A novel mutation of GDAP1 associated with Charcot-Marie-Tooth disease in three Italian families: evidence for a founder effect

Objective: To investigate the role of GDAP1 mutations in causing autosomal recessive neuropathies in an Italian population. Methods and results: 76 patients with severe early onset polyneuropathy and possible autosomal recessive inheritance were screened for mutations. A T>G transversion (c.347 T>G) at codon 116 (M116R) was detected in four affected subjects from three apparently unrelated families. All patients had early onset of disease with pronounced foot deformities and impaired walking. Neurophysiological studies showed an extremely variable expression. Sural nerve biopsies revealed signs of both de-remyelination and axonal impairment, the most prominent feature being a severe loss of larger fibres. Haplotype analysis of the GDAP1 locus demonstrated a common disease haplotype. Conclusions: The association of the mutation with a common haplotype suggested a common ancestor