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Results for “clonal dynamics”

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PubMed2000

Clonal expansions in acute EBV infection are detectable in the CD8 and not the CD4 subset and persist with a variable CD45 phenotype.

We have applied a sensitive global analysis of TCR heterogeneity to compare clonal dynamics of CD4(+) and CD8(+) T cells in acute infectious mononucleosis. Using this approach, we are able to identify a broad representation of the total virus-specific population without the bias of in vitro culture and then to track their phenotype and fate by their unique molecular footprint. We demonstrate a large number of Ag-driven clones using different TCRs in the acute phase, all CD8(+). The diverse large clones generated in the CD8 subset in response to this virus contrast with the complete lack of detectable clonal expansion in the CD4 compartment. Many of the same clones remain detectable in directly ex vivo CD8(+) T cells for at least a year after resolution of infectious mononucleosis, although the clone size is reduced. Thus, memory CD8 cells following EBV infection persist at relatively high circulating frequency and represent a subset of the large range of clonotypes comprising the acute effectors. Separation of samples into CD45RA (naive) and CD45RO (memory) fractions shows the accumulation of identical CDR3 region defined clonotypes in both CD45RO and CD45RA fractions and sequencing confirms that dominant long-lived monoclonal expansions can reside in the CD45RA pool.

Acute Disease↗
PubMed2026

Decoding glioblastoma evolution and heterogeneity through mechanistic modeling: implications for clinical translation.

Glioblastoma (GBM) is one of the most aggressive and lethal primary brain tumors in adults, characterized by dynamic clonal evolution and extensive genomic, cellular, spatial, and microenvironmental heterogeneity. Multi-omics studies have revealed that GBM follows complex evolutionary trajectories involving genetic, epigenetic, transcriptional, and immune-microenvironmental remodeling as tumors grow, adapt to the brain microenvironment, and acquire therapeutic resistance. Increasing evidence suggests that GBM may originate from aberrant neural stem or progenitor cells, including those residing in the subventricular zone, and that glioblastoma stem cells (GSCs) contribute to tumor propagation, heterogeneity, and recurrence. A key conceptual challenge is to reconcile hierarchical cancer stem cell models, in which GSCs are viewed as relatively stable tumor-propagating subpopulations, with dynamic state plasticity models, in which stem-like properties can be reversibly acquired or lost during transitions among proneural-like, mesenchymal-like, invasive, and therapy-tolerant states. Recent advances in single-cell profiling, spatial transcriptomics, lineage tracing, organoid culture, 3D bioprinting, genetically engineered models, and artificial intelligence (AI)-assisted computational modeling have substantially improved the ability to study these processes. However, no currently available model fully recapitulates human GBM heterogeneity, recurrence, treatment history, and tumor-microenvironment interactions. Therefore, model selection should be guided by clearly defined mechanistic questions rather than by reliance on any single platform. This review summarizes current advances in in vitro, ex vivo, in vivo, and computational models for studying GBM evolution and heterogeneity, and discusses how integrated model pipelines may improve preclinical drug testing, treatment-response prediction, and precision neuro-oncology.

Humans↗
PubMed2024

A rapid and simple clonality assay for bovine leukemia virus-infected cells by amplified fragment length polymorphism (AFLP) analysis.

UNLABELLED: Enzootic bovine leukosis (EBL), although eradicated in some European countries, is still the most common neoplastic disease of cattle, caused by the bovine leukemia virus (BLV). During the progression of EBL, BLV-infected cells clonally expand, and some of which result in tumor onset. The clonality of BLV-infected cells is generally evaluated with NGS or Sanger sequencing. Although these methods clearly distinguish EBL from non-EBL cases, the procedures are complex and not practical for routine veterinary diagnosis. In this study, we developed an amplified fragment length polymorphism (AFLP) analysis for BLV clonality assay (BLV-AFLP). This analysis uses restriction enzyme digestion to amplify the chimeric regions of BLV 3' linear transcribed region (LTR) and host genome through conventional polymerase chain reaction (PCR) and visualizes the results by gel-electrophoresis. The method was established using cattle samples representing different stages of the disease: BLV-uninfected, non-EBL, and EBL cattle. Non-EBL cattle showed smeared bands, indicating polyclonal proliferation, while EBL cattle showed distinct bands, indicating clonal expansion. The results of BLV-AFLP correlated well with those of previously reported methods, suggesting its efficacy in detecting clonal proliferation. The validation using blood samples of non-EBL cattle and tumor samples of EBL cattle confirmed that BLV-AFLP could effectively identify clonal proliferation in EBL samples. Moreover, the emergence of dominant clones in the tumor at later stages was successfully detected before EBL onset in some cattle, highlighting its sensitivity and potential for early detection. Overall, BLV-AFLP is suitable for practical use in the field, improving BLV management strategies and minimizing economic losses. IMPORTANCE: Enzootic bovine leukosis (EBL) is routinely diagnosed based on external manifestations at the farm, such as the presence of tumors and/or general lymph node enlargement. However, due to the nonspecific clinical manifestations of EBL, over half of EBL cases are unrecognized at the farm, with most cases being diagnosed during postmortem inspection at the slaughterhouse. Early detection and monitoring of clonal expansion are necessary for managing EBL and reducing economic losses. In this study, we developed BLV-AFLP that represents a significant advancement in the diagnosis of EBL in cattle. This method can rapidly assess the clonal proliferation of BLV-infected cells, crucial for distinguishing between asymptomatic and EBL cattle. Additionally, tracking clonal dynamics offers insights into the disease's progression, potentially providing strategies for avoiding economic losses. Overall, as BLV-AFLP is a simple and rapid test for detecting EBL, it is feasible and efficient for routine veterinary practice.

Leukemia Virus, Bovine↗
PubMed2025

SpaceBar enables clone tracing in spatial transcriptomic data.

We report a cellular barcoding strategy, SpaceBar, that enables simultaneous clone tracing and spatial transcriptomics profiling. Our approach uses a library of 96 synthetic barcode sequences that can be robustly detected by imaging based spatial transcriptomics (seqFISH), delivered such that each cell is labeled with a combination of barcodes. We used these barcodes to label melanoma cells in a tumor xenograft model and profiled both clone identity and spatial gene expression in situ. We developed a gene scoring metric that quantifies how strongly gene expression is driven by intrinsic cellular cues or extrinsic environmental signals. Our framework distinguishes between clonal dynamics and environmentally-driven transcriptional regulation in complex tissue contexts.

Journal Article↗
PubMed2004

Low-dose total body irradiation causes clonal fluctuation of primate hematopoietic stem and progenitor cells.

Due to high frequency of side effects caused by high-dose total body irradiation (TBI) the nonmyeloablative regimen together with cytotoxic agents is currently used especially for elderly patients. However, immediate and long-term effects of low-dose irradiation used in allogeneic transplantation on stem cells is less well known. We have studied the effect of low-dose 3 Gy TBI on the number of hematopoietic stem cell (HSC) clones contributing simultaneously to granulocyte production in rhesus macaque. The number of clones after 3 Gy TBI decreased markedly by 2 to 3 weeks after 3 Gy TBI, followed by a period of clonal instability, and recovery to almost pre-3 Gy TBI clonal diversity. The clones accounting for this recovery contributed before 3 Gy TBI, suggesting the profound initial impact of TBI was on a pool of progenitor cells, whereas most of the more primitive HSCs remained unaffected and were able to again contribute to hematopoiesis after recovery. Clonal fluctuation may indirectly suggest the presence of short-term/long-term HSC populations in rhesus macaque bone marrow as reported in a mouse model. The results indicate that even low-dose irradiation affects hematopoietic clonal dynamics and have implications for design of conditioning regimens for transplantation purposes.

Animals↗
PubMed1985

Organelle motility in rat pituitary clonal cells. I. Dynamic movements of intracellular organelles.

Intracellular organelle motion within clonal pituitary tumor cells (GH3) was observed directly with a contrast enhancement, computer-video microscope system. All particles except nuclei moved in a complex fashion. Two types of particles predominated; one large and round, the other small and elongated. We classified the movements of these particles as saltation, oscillation and slow translocation. Saltation was directional movement with velocity of the order of 1 micron/sec. Oscillation was local motion occurring within 1 micron that showed no specific direction. Its velocity was similar to that of saltation. Large particles, in particular, showed the 3rd type of movement, slow translocation. The velocity appeared to be one order slower than that of saltation. We also examined the cells with fluorescent, dark-field and electron microscopies. We concluded that the large round particles were lysosomes and the small elongated ones mitochondria. The microtubule depolymerizer, vinblastine and the microfilament depolymerizer, cytochalasin D, completely inhibited all the types of organelle movement. The mechanism and significance of these organelle movements are discussed.

Animals↗
PubMed2002

The influence of host dynamics on the clonal composition of Escherichia coli populations.

Species, be they plant or animal, vary in their capacity for population growth or decline. Populations of the same species may also differ in their capacity for population change. A series of mathematical models were developed with the aim of determining if host population dynamics could influence the clonal composition of the Escherichia coli community in that host population. The biological assumptions underlying the models are described in some detail. Analytical and numerical approaches were used to investigate the behaviour of these models. The results demonstrate that host dynamics can have a profound influence on the E. coli clonal composition of the host population. This outcome is largely independent of the nature of the assumptions underlying the models. The ways in which the predictions of these models may be tested empirically are discussed, as are the implications of these models for understanding the nature of host-bacterial pathogen dynamics.

Animals↗
PubMed2004

[Structure and dynamics of Taxus chinensis var. mairei clonal population].

Structure and dynamics of Taxus chinensis var. mairei clonal population were studied. The results showed that according to the life history of Taxus chinensis var. mairei, the modular population could be divided into 6 classes. The development of Taxus chinensis var. mairei population was greatly depended on its ramets, which sprouted on its stem, and the population size structure was stable. The survival curve of Taxus chinensis var. mairei population showed a revered 'J' type. To expanding and continuing the population, there were high ramet sprouting rate and the resource limit induced a higher seedling and sapling mortality rate. When sapling grew up as young tree, its adventitious root stretched into soil to assimilate the nutrient and water, and it became independence individual. Before germination, the seed of Taxus need to dormant for more than one year, and the bird and beast liked to eat the seed, so it was hard to find seedling and sapling from seed. Therefore Taxus chinesis var. mairei had been considered to be a decline or none descendant population. In this study, it was found that Taxus chinensis var. mairei had a powerful asexual multiplication in Yuanbaoshan, especially ramet sprouting on stem. It was depend on this way to develop and expand the population.

Taxus↗
PubMed2003

Nutrient dynamics throughout the rotation of Eucalyptus clonal stands in Congo.

The dynamics of the main nutrient fluxes of the biological cycle were quantified in a clonal Eucalyptus plantation throughout the whole planted crop rotation: current annual requirements of nutrients, uptake from the soil, internal translocations within trees, return to soil (litterfall and crown leaching) and decomposition in the forest floor. As reported for other species, two growth periods were identified in these short-rotation plantations: (1) a juvenile phase up to canopy closure, during which the uptake of nutrients from the soil reserves supplied most of the current requirements; and (2) a second phase up to harvest, characterized by intense nutrient recycling processes. Internal translocation within trees supplied about 30 % of the annual requirements of N and P from 2 years of age onwards, and about 50 % of the K requirement. The mineralization of large amounts of organic matter returned to the soil with litterfall during stand development represented a key process providing nutrients to the stand at the end of the rotation. The importance of the recycling processes was clearly shown by the small amounts of nutrients permanently immobilized in the ligneous components of trees, compared with the total requirements accumulated over the stand rotation which were two to four times higher. Small pools of nutrients circulating quickly in the ecosystem made it possible to produce high amounts of biomass in poor soils. The sustainability of these plantations will require fertilizer inputs that match the changes in soil fertility over successive rotations, mainly linked to the dynamics of organic matter in this tropical soil.

Agriculture↗
PubMed1988

Dynamics of cytotoxic T lymphocyte precursors in vivo assessed by change in the radiation sensitivity. Evidence for development of radiation-sensitive memory cells without clonal expansion.

The dynamics of cytotoxic T lymphocyte precursors (CTL-p) in mice injected with allogeneic spleen cells (SC) was studied with special reference to changes in their radiation sensitivity. Whole-body 400 rad X-ray irradiation of allo-SC-primed and unprimed mice virtually abolished the capacity of their SC to proliferate and to generate CTL in primary or secondary mixed leucocyte culture (MLC). However, the impaired ability of SC to generate CTL in the primary MLC was restored by interleukin 2 (IL-2). This showed that helper cells whose activity was replaceable with IL-2 (IL-2-producing cells) were functionally more radiation-sensitive than CTL-p in unprimed mice. In contrast, the radiation-impaired activity in secondary MLC was not restored by IL-2, suggesting that memory CTL-p in allo-SC-primed mice were unexpectedly sensitive to radiation. The D37 values determined from the percentage of residual CTL-p activity of SC in bulk cultures 1 day after irradiation were 525 rad for virgin CTL-p and 75 rad for memory CTL-p. Further studies demonstrated that the radiation-sensitive memory CTL-p were generated from relatively radiation-resistant precursors, largely independent of radiation-sensitive IL-2-producing cells and of cellular proliferation. The mean frequency of CTL-p in SC measured by limiting dilution assay was not significantly increased by the priming. This supports our conclusion that the development of the memory CTL-p activity in allo-SC-primed mice did not depend on clonal expansion. Whole-body 400 rad-irradiation reduced the frequency of CTL-p in SC from unprimed mice to 1/2-1/3 and that in SC from allo-SC-primed mice to 1/8-1/15. This supports the view that the majority of radiation-resistant virgin CTL-p functionally mature to radiation-sensitive memory CTL-p without cellular proliferation in allo-SC-primed mice.

Animals↗
PubMed2006

Temporal dynamics of genotypic diversity reveal strong clonal selection in the aphid Myzus persicae.

Parthenogenetic organisms often harbour substantial genotypic diversity. This diversity may be the result of recurrent formations of new clones, or it may be maintained by environmental heterogeneity acting on ecological differences among clones. In aphids, both processes may be important because obligate and cyclical parthenogens can form mixed populations. Using microsatellites, I analysed the temporal dynamics of clonal diversity in such a population of the aphid Myzus persicae over a 1-year period. The frequency distribution of clonal genotypes was very skewed, with many rare and few common clones. The relative frequencies of common clones underwent strong and rapid changes indicative of intense clonal selection. Differences in their host associations suggest that these shifts may partly be caused by changes in the abundance of annual host plants. Other selective factors of potential importance are also discussed. New, sexually produced genotypes made a minor contribution to clonal diversity, consistent with the observed heterozygote excess characteristic of predominantly asexual populations in M. persicae.

Animals↗
PubMed1985

Perifusion of a clonal cell line of Simian virus 40-transformed beta cells. Insulin secretory dynamics in response to glucose, 3-isobutyl-1-methylxanthine, and potassium.

A perifusion system for the study of insulin secretory dynamics of a clonal, Simian virus 40-transformed hamster pancreatic beta cell line (HIT cells) is described. After a change from glucose-free to higher glucose levels in the perifusate, insulin secretion increased rapidly in a dose-dependent manner. The pattern of glucose-stimulated insulin release was monophasic and was not sustained during a continued glucose stimulus. Perifusing the cells with low glucose (0.3 mg/ml) before a glucose stimulus of 3.5 mg/ml resulted in more rapid insulin release with lower peak secretory rates than those seen after a glucose-free period. The combined stimulus of high glucose and 100 microM 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor, significantly enhanced the acute insulin secretory response and also resulted in a biphasic secretory pattern that was sustained throughout the 60-min stimulation period. Insulin secretion stimulated by IBMX required a nonstimulatory level of glucose in the perifusing media, and, if this requirement was met, the immediate release of insulin was similar to that evoked by high glucose alone. High potassium (40 mM) also triggered a monophasic release of insulin. These studies demonstrate that glucose or high K+, which depolarizes the plasma membrane, and IBMX, an agent presumed to increase intracellular cyclic AMP levels, can signal the acute release of insulin from these beta cells. This cell line is a unique model system for studying the mechanism of insulin secretion.

1-Methyl-3-isobutylxanthine↗
PubMed1996

Temporal patterns of clonality and parasitism in a population of freshwater bryozoans.

Clonal reproduction is commonly incorporated into the life cycles of many metazoans. However, whether and how such highly clonal animals persist in the face of natural enemies remains poorly understood. Here we report the first temporal genetic study of a clonal population, the freshwater bryozoan Cristatella mucedo, and the associated prevalence of a myxozoan parasite. High levels of both clonality and parasitism persisted over a 3 year period. Random amplified polymorphic DNA markers revealed four distinct clones of C. mucedo. The two most common clones varied in abundance with the significantly more common clone in the first year becoming the significantly less common by the third year. There was no evidence that the most common clone was disproportionately infected. These results are discussed in relation to predictions of the Red Queen and the metapopulation dynamics of clonal organisms.

Animals↗
PubMed2000

Dynamics of genotypic structure in clonal Rhododendron ferrugineum (Ericaceae) populations.

Two populations of Rhododendron ferrugineum growing at subalpine level in the Pyrenees (France) were studied in two sites (Bethmale and Mourtis). Identification and delimitation of genets were inferred from amplified fragment length polymorphism (AFLP) markers, along a closure gradient (from meadow to more closed heath) in each site. Surface and age of genets, genotypic diversity (Simpson's index D), 'proportion distinguishable' genotypes and genetic relationships between genets were then estimated. Amplification of the 312 DNA samples with three selective primer pairs gave a mean of 98 detectable peaks (i.e. bands) per sample, with size ranging from 60 to 300 bp. In total 60% (Bethmale) and 70% (Mourtis) of the peaks were polymorphic, and a total of 31 and 23 multilocus genotypes were identified, in Bethmale and Mourtis, respectively. We inferred that pioneer genotypes began arriving 110 years ago mainly over a 40-year period in the Mourtis meadow, and began about 130 years ago over a 100-year period in the Bethmale meadow. After this pioneer stage, populations extended vegetatively. Two different patterns of genotypic dynamics can be identified. At Bethmale, population closure could have led to a dramatic loss of genets and to the selection of highly genetically related genotypes. In contrast, at Mourtis, genotypic diversity and genet density did not change fundamentally along the closure gradient. However the range of genetic diversity diminished from the open to the closed situation, suggesting that thinning could have occurred in the past.

Ecology↗
PubMed1988

Clonal dominance of primary tumours by metastatic cells: genetic analysis and biological implications.

A new method is described for analysing the clonal evolutionary dynamics of tumour growth and the lineage relationship of primary tumours to their metastases. It exploits random integrations of transfected plasmid or retroviral infected (proviral) DNA as a means of generating very large numbers of uniquely marked cell clones in a single-step selection whose fates can then be tracked during progressive tumour growth. Using a mouse breast adenocarcinoma we undertook experiments in which syngeneic mice were injected with a mixture of very large numbers of uniquely marked cell clones, only one or a few of which were metastatic, or with reconstituted mixtures containing a genetically tagged metastatic clone with an excess of non-marked non-metastatic tumour cells. Among the results we summarize is the finding that spontaneous metastases developed in a non-random fashion from genotypically distinct cell clones. They were clonal or biclonal at the time of analysis. We also found that the progeny of a single metastatic clone could eventually overgrow the primary tumour. Thus malignant (metastatic) cells may manifest a striking growth advantage within the primary tumour site as well as for dissemination and growth at distant, secondary sites. As a result, late-stage advanced primary tumours, if left intact, may evolve to become biologically similar or equivalent to distant metastases. This 'clonal dominance' phenomenon can reconcile many of the discrepant experimental findings with respect to the putative selective nature of metastatic phenotype. Furthermore, it has important consequences for understanding one source of biological variability in experiments in which different primary tumours are compared to each other or to metastases; it also has implications for theories regarding the clonal origin of neoplasms, and for the physiological and biochemical changes that cause malignant disease.

Animals↗
PubMed2003

Rapid turnover of T cells in acute infectious mononucleosis.

During acute infectious mononucleosis (AIM), large clones of Epstein-Barr virus-specific T lymphocytes are produced. To investigate the dynamics of clonal expansion, we measured cell proliferation during AIM using deuterated glucose to label DNA of dividing cells in vivo, analyzing cells according to CD4, CD8 and CD45 phenotype. The proportion of labeled CD8(+)CD45R0(+) T lymphocytes was dramatically increased in AIM subjects compared to controls (mean 17.5 versus 2.8%/day; p<0.005), indicating very rapid proliferation. Labeling was also increased in CD4(+)CD45R0(+) cells (7.1 versus 2.1%/day; p<0.01), but less so in CD45RA(+) cells. Mathematical modeling, accounting for death of labeled cells and changing pool sizes, gave estimated proliferation rates in CD8(+)CD45R0(+) cells of 11-130% of cells proliferating per day (mean 47%/day), equivalent to a doubling time of 1.5 days and an appearance rate in blood of about 5 x 10(9) cells/day (versus 7 x 10(7) cells/day in controls). Very rapid death rates were also observed amongst labeled cells (range 28-124, mean 57%/day),indicating very short survival times in the circulation. Thus, we have shown direct evidence for massive proliferation of CD8(+)CD45R0(+) T lymphocytes in AIM and demonstrated that rapid cell division continues concurrently with greatly accelerated rates of cell disappearance.

Acute Disease↗
PubMed2005

Chromosome abnormalities with prognostic impact in B-cell chronic lymphocytic leukemia.

The detailed analysis of the biologic features led to a rapid increase in clinically relevant information in CLL. The recognition of the prognostic role of IgVH hypermutation status and related phenotypic changes (CD38, ZAP-70 expression) as well as of chromosome abnormalities defined by cytogenetic analysis enabled a refined classification of the disease. Improvements in karyotyping and the introduction of fluorescence in situ hybridization (FISH) in routine hematological diagnostics raised the detection rate of chromosomal aberrations to approx. 60-80% in CLL. Among them, deletions of 17p and 11q have been associated with unfavorable prognosis. The deletion of the p53 locus (17p13) was described as the strongest independent predictor for aggressive behavior, resistance to chemotherapy and early death. On the contrary, an isolated deletion at 13q14 or a normal karyotype was related with a long survival. Classical and molecular cytogenetic analysis became an important tool for individual risk estimation. Unlike any other approaches, cytogenetic monitoring reflects the genetic heterogeneity and clonal growth dynamics during the course of the disease.

ADP-ribosyl Cyclase 1↗