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M Plumb

Publications and source records attributed to M Plumb.

At least 19 recordsLinked to original sources
PubMed2006

Mouse bone marrow and peripheral blood erythroid cell counts are regulated by different autosomal genetic loci.

Erythropoiesis is under fine control and genetic loci that affect it are likely to be important in a range of conditions. To assess the relative contributions of different genetic loci to parameters of erythropoiesis, we have measured RBC counts in the peripheral circulation and committed erythroid cells (RBC and small normoblasts) in the bone marrow in a cohort of (CBA/H x C57BL/6) F2 mice to map quantitative trait loci (QTL). Candidate genes were assessed using bioinformatics and DNA sequencing. Different autosomal loci affect bone marrow (chromosomes 5, 11 and 19) and peripheral blood (chromosome 4) erythroid cell counts but there may be a common chromosome X locus. Spleen weight QTL were found on chromosomes 3, 15 and 17. Surprisingly, erythropoietin (Epo) is the best candidate quantitative trait gene (QTG) in the chromosome 5 locus that affects bone marrow but not peripheral blood erythroid cell counts. Epo gene expression is known to be genetically regulated in mice, but our data suggest a tissue-specific role for epo in mouse erythropoiesis that is also genetically determined. The identity of the other QTG will be important both to further knowledge of the control of erythropoiesis and as potential modifier genes for haematological disorders.

Animals↗
PubMed2001

Allelic loss on chromosome 4 (Lyr2/TLSR5) is associated with myeloid, B-lympho-myeloid, and lymphoid (B and T) mouse radiation-induced leukemias.

The CBA/H mouse model of radiation-induced acute myeloid leukemia (AML) was re-examined using molecular approaches. In addition to the typical promyelocytic AMLs, 34% were reclassified as early pre-B lympho-myeloid leukemias (L-ML) based on leukemic blood cell morphology, immunoglobulin heavy-chain gene re-arrangements (IgH(R)), or expression of both lymphoid (Vpre-B1 and Rag1) and myeloid (myeloperoxidase and lysozyme M) genes. Allelic loss on chromosome 4 was frequently detected in AMLs (53%) and L-MLs (more than 95%), and the preferential loss of the maternally transmitted allele suggests the locus may be imprinted. A minimally deleted region (MDR) maps to a 3.4-cM interval, which is frequently deleted in radiation-induced thymic lymphomas (TLSR5) and contains a recessive, maternally transmitted genetic locus (Lyr2) that confers resistance to spontaneous and radiation-induced pre-B and T cell lymphomas, suggesting they are one and the same. Thus, the Lyr2/TLSR5 locus is frequently implicated in myeloid, lymphoid (B and T), and mixed-lineage mouse leukemias and lymphomas. Epigenetic inactivation of one Lyr2/TLSR5 allele during normal mouse development suggests that only a single hit is required for its inactivation during leukemogenesis, and this may be a significant contributing factor to the efficiency of the leukemogenic process in the mouse.

Acute Disease↗
PubMed2001

Susceptibility to radiation-induced leukaemia/lymphoma is genetically separable from sensitivity to radiation-induced genomic instability.

PURPOSE: To determine whether there is a relationship between the genetics underlying the susceptibility to radiation-induced leukaemia in CBA/H (acute myeloid leukaemia, AML) and C57BL/6 (thymic lymphoma, TL) mice, and the genetics underlying the sensitivity of CBA/H (sensitive) and C57BL/6 (resistant) mice to radiation-induced chromosomal instability. MATERIALS AND METHODS: CBA/H, (CBA/H x C57BL/6)F1, F1 x CBA/H, F1 x C57BL/6 and F1 x F1 mice were exposed to a single acute dose of 3.0 Gy X-rays. AML and TL were diagnosed over the subsequent 30 months. RESULTS: There was no statistically significant difference in the incidence of AML in F1, F1 x F1, F1 x CBA/H and F1 x C57BL/6 mice, which was approximately 50% that in CBA/H mice. AML susceptibility is therefore a dominant polygenic trait, and both susceptibility and resistance (variable penetrance) CBA/H and C57BL/6 loci are involved. The incidence of TL in the FM and F1 x CBA/H mice was negligible, indicating that TL susceptibility is a recessive trait. As the TL incidence in the F1 x C57BL/6 mice was about half that in C57BL/6 mice, one recessive locus is probably involved. CONCLUSIONS: AML susceptibility in CBA/H mice is a dominant trait in contrast to the recessive inheritance of CBA/H sensitivity to radiation-induced chromosomal instability. TL-susceptibility in C57BL/6 is a recessive trait in contrast to the dominant inheritance of C57BL/6 resistance to radiation-induced chromosomal instability.

Animals↗
PubMed2001

Evidence of genetic instability in 3 Gy X-ray-induced mouse leukaemias and 3 Gy X-irradiated haemopoietic stem cells.

PURPOSE: If radiation-induced genetic instability is causal in mouse radiation leukaemogenesis, then genetic instability should be detectable in the irradiated target untransformed haemopoietic stem cell, and evidence of genetic instability detected in the clonal radiation-induced leukaemia. We have tested this hypothesis using the CBA/H mouse model of radiation-induced acute myeloid leukaemia (r-AML). MATERIALS AND METHODS: Fluorescence in situ hybridisation (FISH) was employed to screen for chromosomal aberrations in mouse 3 Gy X-ray-induced r-AMLs and in the clonal descendents of control and 3 Gy X-irradiated bone marrow haemopoietic stem cells using the in vitro clonogenic CFU-A colony assay. RESULTS: High levels of clonal non-specific chromosomal aberrations were detected in the r-AML (approximately 4-5 aberrations/r-AML), and ongoing chromosomal instability as defined by subclonal variants detected in 5/10 r-AML. A similar analysis of CFU-A colonies revealed chromosomal aberrations in 25% of colonies derived from irradiated bone marrow (2% in controls). However, 66% of the aberrant colonies (2% in controls) exhibited ongoing genetic instability as defined by non-clonal chromosomal aberrations. Overall, 6% (121/1884) of the CFU-A cells derived from irradiated bone marrow were aberrant (0.05% in controls) of which 12% (15/121) were subclonal. No one CFU-A cell exhibited aberrations on more than one of the three chromosomes painted. CONCLUSIONS: The high levels of non-specific genetic damage observed in the r-AMLs is therefore attributed to the accumulation of genetic lesions in the target haemopoietic stem cell over a longer time-scale after exposure than assessed in the in vitro CFU-A clonogenic assay. This is consistent with the long latency of the multi-stage radiation leukaemogenic process, and a role for radiation-induced genetic instability is inferred.

Animals↗
PubMed2001

Undercounts and overstatements: will the IOM report on lesbian health improve research?

In January 1999, the Institute of Medicine (IOM) released a report on lesbian health research that fulfills 3 goals: it provides an extensive review of much of the research that has been done on the health of women who have sex with other women, it addresses the methodological and ethical issues inherent in conducting research on this population, and it suggests avenues for further research. This report will likely help lesbian health researchers gain funding, publish further research in medical journals, and receive support and validation from medical and research institutions. To ensure that such research is useful, benefits the lesbian community, and expands the understanding of lesbian health conditions, particular attention needs to be paid to the methods and definitions used and to the involvement of the lesbian community in designing, implementing, and analyzing the research itself.

Community Health Planning↗
PubMed2000

No correlation between germline mutation at repeat DNA and meiotic crossover in male mice exposed to X-rays or cisplatin.

To test the hypothesis that mouse germline expanded simple tandem repeat (ESTR) mutations are associated with recombination events during spermatogenesis, crossover frequencies were compared with germline mutation rates at ESTR loci in male mice acutely exposed to 1Gy of X-rays or to 10mg/kg of the anticancer drug cisplatin. Ionising radiation resulted in a highly significant 2.7-3.6-fold increase in ESTR mutation rate in males mated 4, 5 and 6 weeks after exposure, but not 3 weeks after exposure. In contrast, irradiation had no effect on meiotic crossover frequencies assayed on six chromosomes using 25 polymorphic microsatellite loci spaced at approximately 20cM intervals and covering 421cM of the mouse genome. Paternal exposure to cisplatin did not affect either ESTR mutation rates or crossover frequencies, despite a report that cisplatin can increase crossover frequency in mice. Correlation analysis did not reveal any associations between the paternal ESTR mutation rate and crossover frequency in unexposed males and in those exposed to X-rays or cisplatin. This study does not, therefore, support the hypothesis that mutation induction at mouse ESTR loci results from a general genome-wide increase in meiotic recombination rate.

Animals↗
PubMed2000

Induction of minisatellite mutations in the mouse germline by low-dose chronic exposure to gamma-radiation and fission neutrons.

Germline mutation induction at mouse minisatellite loci by paternal low-dose (0.125-1 Gy) exposure to chronic (1.66 x 10(-4) Gy min(-1)) low-linear energy transfer (low-LET) gamma-irradiation and high-LET fission neutrons (0.003 Gy min(-1)) was studied at pre-meiotic stages of spermatogenesis. Both types of radiation produced linear dose-response curves for mutation of the paternal allele. In contrast to previous results using higher doses, the pattern of induction of minisatellite mutation after chronic gamma-irradiation was similar to acute (0.5 Gy min(-1)) exposure to X-rays, indicating that the elevated mutation rate was independent of the ability of the cell to repair damage induced immediately or over a period of up to 100 h. Chronic exposure to fission neutrons was more effective than acute or chronic low-LET exposure (relative biological effectiveness, RBE=3.36). The data also provide strong support for the previous conclusion that increases in minisatellite mutation rate are not caused by radiation-induced DNA damage at minisatellite loci themselves, but rather from damage induced by ionising radiation elsewhere in the genome/cell.

Animals↗
PubMed1999

An E mu-BCL-2 transgene facilitates leukaemogenesis by ionizing radiation.

Clonogenic murine B cell precursors are normally ultrasensitive to apoptosis following genotoxic exposure in vitro but can be protected by expression of an E mu-BCL-2 transgene. Such exposures are likely to be mutagenic. This in turn suggests that a level of in vivo genotoxic exposure that usually has minimal pathological consequences might become leukaemogenic when damaged cells fail to abort by apoptosis. If this were to be the case, then the cell type that becomes leukaemic and the chromosomal/molecular changes that occur would also be of considerable interest. We tested this possibility by exposing E mu-BCL-2 and wild-type mice of differing ages to a single dose of X-irradiation of 1-4 Gy. Young (approximately 4-6 weeks) transgenic mice developed leukaemia at a high rate following exposure to 2 Gy but adult mice (4-6 months) did not. Exposure to 4 Gy produced leukaemia in both young and adult transgenic mice but at a higher frequency in the former. Leukaemic cell populations showed clonal rearrangements of the IGH gene but in most cases analysed had immunophenotypic features of an early B lympho-myeloid progenitor population which has not previously been recorded in radiation leukaemogenesis. Molecular cytogenetic analysis of leukaemic cells by banded karyotype and FISH revealed a consistent double abnormality: trisomy 15 plus an interstitial deletion of chromosome 4 that was confirmed by LOH analysis.

Animals↗
PubMed1999

Allelic loss and promoter hypermethylation of the p15INK4b gene features in mouse radiation-induced lymphoid - but not myeloid - leukaemias.

Mouse radiation-induced acute myeloid leukaemias (AMLs) which arose in a (CBA/H x C57BL/6) genetic background have a 45% incidence of loss of heterozygosity (LOH) on chromosome 4. Frequent chromosome 4 LOH in mouse radiation-induced (C57BL/6 x RF/J) thymic lymphomas (TLs) is associated with promoter/exon 1 region hypermethylation of the remaining p15INK4b and p16INK4a alleles, so this may be common to mouse radiation myeloid and lymphoid leukaemogenesis. We addressed the question of p15INK4b/p16INK4a/p19ARF gene promoter hypermethylation in radiation-induced AMLs by comparison to TLs which arose in a similar (C57BL/6 x CBA/H) genetic background as a consequence of the same initiating dose of 3 Gy X-rays. Only one homozygous deletion was detected in the approximately 100 leukaemias analysed. p15INK4b gene promoter/exon 1 hypermethylation was readily detected (21%) in the lymphoid but not myeloid (3.1%) leukaemias, and p16INK4a and p19ARF gene promoter/exon 1 methylation was rare (<3%) in both. Thus, allelic loss and promoter hypermethylation of the p15INK4b gene is particular to radiation-induced lymphoid leukaemias and is independent of p16INK4a and p19ARF gene promoter/exon 1 hypermethylation.

Alleles↗
PubMed1999

Specificity of loss of heterozygosity in radiation-induced mouse myeloid and lymphoid leukaemias.

PURPOSE: To determine whether loss of heterozygosity (LOH) at specific chromosomal loci in radiation-induced leukaemias, arising in a similar genetic background, is leukaemia-type specific (myeloid versus lymphoid) or common to both. MATERIALS AND METHODS: Leukaemias that arose in 3 Gy X-irradiated (CBA/H x C57BL/6)F1 intercross and backcross mice were diagnosed as acute myeloid leukaemia (AML) or thymic lymphoma (TL). LOH was determined using 28 polymorphic microsatellite markers distributed over seven chromosomes using control and leukaemic DNA from individual mice. RESULTS: LOH incidences of 0-20% were observed at most loci in both leukaemia types. Specific LOH incidences of 38-76% were observed for myeloid (chromosome 2) and lymphoid (chromosomes 11 and 14) leukaemias. Chromosome 4 LOH was frequently (38-50%) observed in both types, although the commonly deleted regions differed. LOH was detected at either chromosome 2 or 4 in AML and either chromosome 4 or 11 in TL. CONCLUSIONS: LOH incidences of 38-76% suggest a causal role of particular loci which is mainly, but not exclusively, dependent on leukaemia type. LOH incidences of 0-20% at other loci in both leukaemias suggest that many genetic deletions are non-causal and incidental in radiation-leukaemogenesis.

Animals↗
PubMed1998

Stage specificity, dose response, and doubling dose for mouse minisatellite germ-line mutation induced by acute radiation.

Germ-line mutation induction at mouse minisatellite loci by acute irradiation with x-rays was studied at premeiotic and postmeiotic stages of spermatogenesis. An elevated paternal mutation rate was found after irradiation of premeiotic spermatogonia and stem cells, whereas the frequency of minisatellite mutation after postmeiotic irradiation of spermatids was similar to that in control litters. In contrast, paternal irradiation did not affect the maternal mutation rate. A linear dose-response curve for paternal mutation induced at premeiotic stages was found, with a doubling dose of 0.33 Gy, a value close to those obtained in mice after acute spermatogonia irradiation using other systems for mutation detection. High frequencies of spontaneous and induced mutations at minisatellite loci allow mutation induction to be evaluated at low doses of exposure in very small population samples, which currently makes minisatellite DNA the most powerful tool for monitoring radiation-induced germ-line mutation.

Animals↗
PubMed1998

Radiation-induced germline instability at minisatellite loci.

PURPOSE: To review the results of recent studies on radiation-induced germline instability at mammalian minisatellite loci. RESULTS: Evidence has been obtained recently that germline mutation at minisatellites is remarkably sensitive to ionizing radiation, in both mice and humans. In mice, an elevated mutation rate was found after acute irradiation of pre-meiotic spermatogonia, with a doubling dose of 0.33 Gy, a value close to those obtained in mice after acute spermatogonia irradiation using other systems for mutation detection. In humans, analysis of germline mutation rate at minisatellites among children born in areas of the Mogilev district of Belarus, which was heavily polluted after the Chernobyl accident, has shown a twofold higher mutation rate in exposed families compared with non-irradiated families from the United Kingdom. Within the Belarus cohort, the mutation rate was significantly greater in families exposed to a higher parental radiation dose, consistent with radiation induction of germline mutation. The data in this study also demonstrate the indirect nature of radiation-induced germline mutation at mammalian minisatellite loci suggesting a strong similarity with the phenomenon of genomic instability in somatic cells. CONCLUSIONS: Minisatellite loci provide a powerful system for the efficient monitoring of germline mutation in humans and are capable of detecting induced mutations in relatively small population samples.

Animals↗
PubMed1998

Genetic instability in radiation-induced leukaemias: mouse models.

PURPOSE: Genetic instability plays a major role in multi-stage carcinogenesis. Ionizing radiation induces delayed genetic instability which can be transmitted to the clonal offspring of the irradiated cell, so it is of considerable importance to determine whether radiation-induced genetic instability contributes to radiation-leukaemogenesis. RESULTS: The experimental data obtained using radiation-induced leukaemias in mouse models were reviewed, and an attempt was made to distinguish between the instability detectable in de novo cancers and that which is associated with ionising radiation. Genetic lesions identified in mouse leukaemias include non-clonal chromosomal aberrations, loss of heterozygosity, and minisatellite/microsatellite mutations. CONCLUSIONS: Studies of mouse radiation-induced leukaemias have detected evidence of genetic instability. However, with few exceptions, most of this instability was also observed during de novo multi-stage carcinogenesis. This raises the possibility that radiation induces ongoing genetic instability that is functionally indistinguishable to that implicated in de novo tumour progression.

Animals↗
PubMed1997

Mini- and microsatellite mutations in radiation-induced acute myeloid leukaemia in the CBA/H mouse.

Radiation-induced acute myeloid leukaemia (AML) in the CBA/H mouse is a clonal disorder and therefore amenable to the analysis of genetic instability during radiation leukaemogenesis. The genotype of a single minisatellite and 20 microsatellite loci was compared in tail and leukaemic spleen DNA prepared from the same mouse. Somatic mutation at the Ms6-hm minisatellite locus was nearly seven times higher (27%, 4/15) than the spontaneous germline mutation rate (4%). Only 1/15 AMLs exhibited microsatellite mutations, but 5/20 loci were mutated in the same AML, indicating that it was deficient in mismatch repair. Thus, whereas somatic minisatellite mutations, which are associated with complex intra-allelic gene conversion events, occur at a very high rate in the radiation-induced AMLs, microsatellite instability, which has been associated with the acquisition of the replication error repair (RER+) phenotype, is infrequent but detectable.

Acute Disease↗
PubMed1997

Ongoing Y-chromosome instability defines sub-clonal variants in radiation-induced leukaemias in the mouse.

Forty primary leukaemias that arose in vivo as a consequence of 3 Gy X-irradiation of inbred mouse strains were analysed for Y-chromosome aberrations by conventional cytogenetics and fluorescent in situ hybridization (FISH). Compared with control mice which were X-irradiated but which exhibited no overt signs of leukaemia, the loss and gain of Y-chromosomes in leukaemic spleen cells defined subclonal variants in the radiation-induced haemopoietic malignancies that arose in CBA/H, DBA/2 and (C57BL/6 x DBA/2)F1 mice. This Y-chromosome instability was significantly higher than that observed in spleen cells of age-matched (or older) irradiated control mice that had not developed overt leukaemia. The detection of Y-chromosome aberrations is considered in the context of the high numbers of potential gene regulatory sequences in the murine Y-chromosome and the potential for the insertional activation of cellular genes during multi-stage radiation leukaemogenesis.

Acute Disease↗
PubMed1996

A polymorphic and hypervariable locus in the pseudoautosomal region of the CBA/H mouse sex chromosomes.

We have identified a genomic locus (DXYH1) that is polymorphic and hypervariable within the CBA/H colony. Using a panel of C57BL/6 x Mus spretus backcross offspring, it was mapped to the distal end of the X chromosome. Pseudoautosomal inheritance was demonstrated through three generations of CBA/H x CBA/H and CBA/H x C57BL/6 crosses and confirmed through linkage to the Sxr locus in X/Y Sxr x 3H1 crosses. Meiotic recombination frequencies place DXYH1 similar 28% into the pseudoautosomal region from the boundary. The de novo generation of CBA/H variant DXYH1 restriction fragment length polymorphisms during spermatogenesis is suggestive of the germline instability associated with hypermutable human minisatellites. The absence of DXYH1-related sequences in Mus spretus provides DNA sequence evidence to support the observed failure of X-Y pairing during meiosis and consequent hybrid infertility in C57BL/6 x Mus spretus male F1 offspring.

Animals↗