Biomedical subjects

Alexander A Morley

Publications and source records attributed to Alexander A Morley.

4 recordsLinked to original sources

PubMed2003

Mitotic recombination is an important mutational event following oxidative damage.

The mutagenic effects of hydrogen peroxide (H(2)O(2)), a source of reactive oxygen species (ROS) have been determined in human lymphocytes. T-lymphocytes mutated at the autosomal HLA-A locus on chromosome 6 have been clonally isolated (N = 2097 clones) and the molecular basis of each clonal mutation characterised as due to intragenic, deletion or mitotic recombination mutation. H(2)O(2) caused a dose dependent increase in mutation frequency. There was no significant increase in the frequency of intragenic mutations. Mitotic recombination (MR) was responsible for 87% of the increase in mutation frequency induced by H(2)O(2) and gene deletion was responsible for 13%. MR results in loss of heterozygosity (LOH) distal to the recombination site. It is known that LOH is important in the initiation and progression of cancer. These results suggest that the biologically important consequence of some ROS may be LOH as a by-product of recombination repair. They also suggest that if our observations apply to ROS generally, then many of the mutations which accumulate with ageing or which are observed in cancer may be due to factors other than ROS.

DNA Damage↗

PubMed2003

Evidence for whole chromosome 6 loss and duplication of the remaining chromosome in acute lymphoblastic leukemia.

HLA class I molecules serve the essential immunological function of presenting antigen to CD8+ T lymphocytes. Tumor cells may present tumor-specific antigen to T cells via these molecules, but many tumors show a loss or down-regulation of HLA class I expression and this may serve as an immune escape mechanism. Using a microsatellite marker-based method, we have searched for loss of heterozygosity (LOH) mutations at 3 genomic regions implicated in HLA class I expression in a cohort of 56 acute lymphoblastic leukemia (ALL) samples. The regions analyzed consisted of the HLA class I heavy chain genes located within the MHC genomic region on chromosome arm 6p, the HLA class I light chain (beta-2-microglobulin, B2M) gene on chromosome arm 15q, and the putative HLA modifier of methylation gene (MEMO1) located on chromosome arm 1q. Results revealed low frequencies of B2M (2/55) and MEMO1 (5/42) LOH but a high frequency of MHC LOH (19/56) that was usually associated with whole chromosome 6 loss (13/19). Cytogenetic data were available for 30 samples, including nine of those that exhibited apparent whole chromosome 6 loss. No cases of chromosome 6 monosomy were observed. We propose that whole chromosome 6 loss with reduplication of the remaining chromosome is common in ALL and that it is driven by the presence of tumor-inhibiting factors on chromosome arm 6p (the HLA loci) along with previously localized tumor-suppressor genes on chromosome arm 6q.

Adult↗

PubMed2003

Modelling a minimal residual disease-based treatment strategy in childhood acute lymphoblastic leukaemia.

The measurement of minimal residual disease (MRD) in childhood acute lymphoblastic leukaemia offers the promise of individualized, risk-stratified treatment, but an optimal protocol needs establishing. A model was developed to explore certain unanswered questions. The model assumes that all patients have MRD assessed after induction chemotherapy and children above a certain threshold are offered intensive chemotherapy. Using parameter estimates derived from published studies of MRD, the model predicted event-free survival (EFS) rates, relapse rates and treatment-related mortality for a cohort of children in the first presentation who were Philadelphia chromosome negative. Using the level of MRD after induction in order to decide on the use of intensive therapy resulted in an increase in EFS rates of up to 2.9 per 100 children, although if the error of the MRD measurement were too great, the benefit was almost nullified. Taking and analysing more than one marrow sample from the patient for the MRD measurement, in order to reduce sampling and measurement error, improved EFS by a further 1.1 patients per 100 treated, and decreased the number of patients offered intensive therapy by up to 2.6 per 100 treated. The optimal threshold for offering intensive therapy was in the range of 10-3.5- 10-4.5 cells if the intensive treatment-related mortality was 13-18% (allograft options), but 10-5- 10-6 cells if it was less than 8% (intensified chemotherapy). Using MRD to target patients at a high risk of relapse improved EFS rates, but the accuracy of measurements was of critical importance.

Antineoplastic Agents↗

PubMed2002

Dose-dependent increase or decrease of somatic intrachromosomal recombination produced by etoposide.

Chromosomal inversions and deletions can occur via somatic intrachromosomal recombination (SICR), a mechanism known to be important in mutagenesis and carcinogenesis. Here, we demonstrate a dose-dependent increase or decrease in SICR inversion frequency both in vivo and in vitro after treatment with etoposide, using the pKZ1 mouse mutagenesis model. pKZ1 mice received a single intraperitoneal injection of etoposide dose ranging from 0.0005 to 50mg/kg. Animals were sacrificed 3 days after treatment and the spleen was analysed for SICR. A significant 1.4-3.1-fold induction of SICR inversion events was detected in pKZ1 mice after treatment with etoposide doses ranging from 0.05 to 50 mg/kg etoposide. However, inversion frequencies after treatment with 0.0005 and 0.005 mg/kg etoposide decreased significantly to 0.67 and 0.43 of the levels observed in control animals, respectively. A pKZ1 mouse hybridoma cell line was exposed to etoposide (1-1000 nM) and a similar pattern of SICR response to that detected in vivo was observed. A significant 2.3-4.6-fold induction of SICR inversions was observed in pKZ1 cells treated with 100 and 1000 nM etoposide. Inversion frequencies after treatment with 1 and 10nM etoposide decreased significantly to 0.31 and 0.5 of the level observed in control cell lines. Our in vitro studies complement our in vivo studies and exclude a kinetic phenomenon as the responsible mechanism of reduction in SICR in response to low dose etoposide. Determination of the exact mechanism and significance of recombination suppression at low doses of etoposide treatment requires further investigation.

Animals↗