Strain Background Determines Lymphoma Incidence in Atm Knockout Mice

Genik, Paula C.; Bielefeldt‐Ohmann, Helle; Liu, Xianan; Story, Michael D.; Ding, Lianghao; Bush, Jamie M.; Fallgren, Christina M.; Weil, Michael M.

doi:10.1593/neo.131980

Cited by 21 publications

(19 citation statements)

References 27 publications

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“…Atm −/− mice consistently develop thymic lymphoma early in life, and almost all Atm −/− mice die of these cancers [ 24 ]. During autopsy of the mice in the blood glutamine study, we noted variability in the extent of the visible thymic pathology.…”

Section: Resultsmentioning

confidence: 99%

The impact of glutamine supplementation on the symptoms of ataxia-telangiectasia: a preclinical assessment

Chen

Vail

et al. 2016

Mol Neurodegeneration

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BackgroundOur previous studies of Alzheimer’s disease (AD) suggested that glutamine broadly improves cellular readiness to respond to stress and acts as a neuroprotectant both in vitro and in AD mouse models. We now expand our studies to a second neurodegenerative disease, ataxia-telangiectasia (A-T). Unlike AD, where clinically significant cognitive decline does not typically occur before age 65, A-T symptoms appear in early childhood and are caused exclusively by mutations in the ATM (A-T mutated) gene.ResultsGenetically ATM-deficient mice and wild type littermates were maintained with or without 4 % glutamine in their drinking water for several weeks. In ATM mutants, glutamine supplementation restored serum glutamine and glucose levels and reduced body weight loss. Lost neurophysiological function assessed through the magnitude of hippocampal long term potentiation was significantly restored. Glutamine supplemented mice also showed reduced thymus pathology and, remarkably, a full one-third extension of lifespan. In vitro assays revealed that ATM-deficient cells are more sensitive to glutamine deprivation, while supra-molar glutamine (8 mM) partially rescued the reduction of BDNF expression and HDAC4 nuclear translocation of genetically mutant Atm−/− neurons. Analysis of microarray data suggested that glutamine metabolism is significantly altered in human A-T brains as well.ConclusionGlutamine is a powerful part of an organism’s internal environment. Changes in its concentrations can have a huge impact on the function of all organ systems, especially the brain. Glutamine supplementation thus bears consideration as a therapeutic strategy for the treatment of human A-T and perhaps other neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

The impact of glutamine supplementation on the symptoms of ataxia-telangiectasia: a preclinical assessment

Chen

Vail

et al. 2016

Mol Neurodegeneration

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“…This region includes the genes encoding MRE11 and CHK1. Chromosome 9 amplification appears to be unique to Nbn −/mid8vav tumors, as amplification of this region has not been observed in thymic lymphomas from TP53-or ATM-deficient mice (28)(29)(30). Thus, the evolution of Nbn −/mid8vav malignancy is distinct.…”

Section: Resultsmentioning

confidence: 97%

Nbn−Mre11 interaction is required for tumor suppression and genomic integrity

Kim

Penson

Taylor

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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We derived a mouse model in which a mutant form of Nbn/Nbs1mid8 (hereafter Nbnmid8) exhibits severely impaired binding to the Mre11−Rad50 core of the Mre11 complex. The Nbnmid8 allele was expressed exclusively in hematopoietic lineages (in Nbn−/mid8vav mice). Unlike Nbnflox/floxvav mice with Nbn deficiency in the bone marrow, Nbn−/mid8vav mice were viable. Nbn−/mid8vav mice hematopoiesis was profoundly defective, exhibiting reduced cellularity of thymus and bone marrow, and stage-specific blockage of B cell development. Within 6 mo, Nbn−/mid8 mice developed highly penetrant T cell leukemias. Nbn−/mid8vav leukemias recapitulated mutational features of human T cell acute lymphoblastic leukemia (T-ALL), containing mutations in NOTCH1, TP53, BCL6, BCOR, and IKZF1, suggesting that Nbnmid8 mice may provide a venue to examine the relationship between the Mre11 complex and oncogene activation in the hematopoietic compartment. Genomic analysis of Nbn−/mid8vav malignancies showed focal amplification of 9qA2, causing overexpression of MRE11 and CHK1. We propose that overexpression of MRE11 compensates for the metastable Mre11−Nbnmid8 interaction, and that selective pressure for overexpression reflects the essential role of Nbn in promoting assembly and activity of the Mre11 complex.

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“…[29,30] Indeed, in one study, ATM knockout mice of different strains weighed on average, 72-87% as much as atm +/+ mice of the same sex and strain at ve weeks of age. [31] Height faltering in classic A-T occurs in essentially every patient with classic A-T and is an unrelenting problem. This faltering appears to worsen in adolescence -a period when a growth spurt occurs in the unaffected population.…”

Section: Discussionmentioning

confidence: 99%

Growth in ataxia telangiectasia

Natale¹,

Cole

Rothblum-Oviatt

et al. 2020

Preprint

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Background Ataxia telangiectasia (A-T) is a DNA repair disorder that affects multiple body systems. Neurological problems and immunodeficiency are two important features of this syndrome. At this time, two main severity groups are defined in A-T: classic (the more severe form) and mild. Poor growth is a common problem in classic A-T. An objective of this study was to develop growth references for classic A-T. Another objective was to compare growth patterns in classic A-T and mild A-T with each other and with the general population, using the CDC growth references. A final objective was to examine the effects of chronic infection on height. Results We found that classic A-T patients were smaller overall, and suffered from height and weight faltering that continued throughout childhood and adolescence. When compared to the CDC growth references, the median heights and weights for both male and female patients eventually fell to or below the 3rd centile on the CDC charts. Height faltering was more pronounced in females. Birthweight was lower in the classic A-T group compared to mild A-T and the general population, whereas birth length was not. Finally, we investigated height and BMI faltering in relation to number of infections and found no association. Conclusions Classic A-T appears to affect growth in utero. Although children appear to grow well in very early life, faltering begins early and is unrelenting.

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Strain Background Determines Lymphoma Incidence in Atm Knockout Mice

Cited by 21 publications

References 27 publications

The impact of glutamine supplementation on the symptoms of ataxia-telangiectasia: a preclinical assessment

The impact of glutamine supplementation on the symptoms of ataxia-telangiectasia: a preclinical assessment

Nbn−Mre11 interaction is required for tumor suppression and genomic integrity

Growth in ataxia telangiectasia

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