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At least 19 recordsLinked to original sources
PubMed2026

Aging and DNA damage are associated with the development of endothelial cell clonal expansion.

Endothelial dysfunction is a hallmark of vascular aging and a key contributor to cardiovascular disease. Although senescence has been widely studied as a terminal endothelial cell fate, recent evidence suggests that clonal expansion, the proliferative expansion of genetically identical cells, may also occur in aged tissues. We sought to determine whether endothelial clonal expansion increases with age, specifically at the atheroprone regions of the aorta, and to evaluate whether DNA damage promotes endothelial cell clonal expansion. Tamoxifen-inducible, endothelial-specific Cdh5-CreERT2 male and female mice were used to quantify clonal expansion in endothelial cells (ECs) across the aortic region in both young (4 mo) and aged (24 mo) mice. We further examined the effect of DNA damage by administering systemic doxorubicin (DOXO) to assess clonal dynamics in different aortic regions. Aging significantly increased EC clone size and the percentage of clonal ECs in atheroprone regions, particularly the minor arch, whereas only clone size increased in nonatheroprone regions. Systemic DOXO administration increased clone size across the aortic region without altering clonal recruitment, indicating selective amplification of preexisting clones. These findings suggest that clonal expansion is promoted by both aging and DNA damage. Clonal expansion may represent an underrecognized mechanism contributing to endothelial homogeneity and vascular remodeling during aging and in response to sublethal genomic stress.NEW & NOTEWORTHY Aging reshapes the vascular endothelium in unexpected ways. Using lineage tracing in mice, we show that endothelial cells undergo age-dependent clonal expansion, particularly in atheroprone regions exposed to disturbed blood flow. This process is amplified by DNA damage and reflects the selective expansion of preexisting clones rather than increased recruitment. Endothelial clonal expansion may represent an underrecognized mechanism driving vascular remodeling during aging and genotoxic stress.

Animals↗
PubMed1979

Prostaglandin E inhibition of T-lymphocyte colony formation: a possible mechanism of monocyte modulation of clonal expansion.

Prostaglandin and monocyte modulation of a T-lymphocyte cell capable of undergoing clonal expansion was studied. Circulating human mononuclear cells were isolated by density centrifugation. After 24 h in culture with phytohemagglutinin present, the cells were mixed with 0.3% agar and overlayed onto a 0.5% agar layer that contained media and phytohemagglutinin. At day 6, colonies that contained greater than 50 cells were counted. These colonies represented clonal prolifertion of a phytohemagglutinin-responsive T-lymphocyte precursor. This responder cell accounted for less than 0.3% of the starting cell population. Colonies were comprised of cells which, when isolated, formed E rosettes. These colony cells could be shown to have helper or suppressor function as measured by their ability to promote or inhibit immunoglobulin synthesis. By these latter criteria the colony cells were considered to be mature T lymphocytes. The addition of prostaglandin E to the cultures demonstrated a linear, r = 0.82, dose-dependent inhibition of colony formation with a 50% point of inhibition (I50) = 0.18 muM. Low numbers of normal monocytes when added to the cultures mimicked the effect of synthetic prostaglandin E2. A highly significant correlation could be shown for endogenous prostaglandin E levels and colony counts. It appears that monocytes through their synthesis of prostaglandin E2 can restrict the clonal expansion of a circulating T-lymphocyte precursor.

Adult↗
PubMed1978

Clonal expansion and progression in acute myeloblastic leukemia.

Diseaes originating in pluripotent stem cells, then developing through clonal expansion and clonal progression may properly be grouped together because of their common features. Among these, AML appears to be unique by reason of the presence within the clone of a blast cell population. Studies of cellular composition and regulation in AML clones require assays that measure not only myelopoiesis but also blast cell proliferation. The relation of the blast population to other components of AML clones remains uncertain. Resolution of the uncertainty is important in considering therapeutic strategies.

Bone Marrow Cells↗
PubMed2026

Clonotypic characterization defines B-cell drivers of clonal expansion and intratumor heterogeneity in IgM monoclonal gammopathies.

Waldenström macroglobulinemia (WM) and IgM monoclonal gammopathy of undetermined significance (MGUS) share the same cell of origin but differ in clonal size. Compared with other B-cell neoplasms, the lymphoplasmacytic clone in WM can be rather small, limiting our understanding of clonal expansion. We applied an integrative approach using single-cell RNA with B-cell receptor (BCR) sequencing, the assay for transposase-accessible chromatin, and whole-genome sequencing to characterize the tumor clone in patients with IgM MGUS, smoldering WM (SWM), and symptomatic WM (WM). IgM MGUS and low- or intermediate-risk SWM harbored multiple B-cell clones compared to WM. CD9, JCHAIN, RASSF6, and DUSP22 were the main markers of the dominant B-cell clone at gene expression and chromatin activity levels, with CD9 preferentially expressed in plasma cell-like tumor cells. POU2F2 had high activity in the tumor clone and was linked to CD9 regulatory regions. MYD88 and IGLL5 mutations, mainly associated with the mutational signature SBS5, were present in minor clones, whereas the MYD88 mutation was also detected in nonexpanded B-cells. The 6q deletion was present in tumor cells from high-risk patients, which harbored fitness advantage over copy-neutral tumor cells. Coding mutations clustered tumor and minor clones from oligoclonal patients and were associated with abnormal transcriptional programs. The B-cell clones also showed enriched predicted interactions with monocytes. Our integrative single-cell approach reveals the importance of clone size in IgM gammopathy and identifies key markers promoting clonal expansion.

Journal Article↗
PubMed1976

Studies on T cell clonal expansion. II. The in vitro differentiation of pre-killer and memory T cells.

Spleen cells from C57BL/6 mice immunized with a DBA/2 mastocytoma (P815) were harvested at various stages of the immune response and cultured in vitro in the presence and absence of antigen. Killer T cell activity in immune spleens could not be demonstrated until 6 or 7 days after antigen, but spleen cells harvested as early as 3 or 4 days and cultured for 24 hr at 37 degrees C showed significant cytotoxicity. This increased activity was not augmented further by culturing with antigen. "Memory" T cells, whose in vitro differentiation into killer cells required the presence of antigen, could not be demonstrated until 9 or 10 days after alloantigenic stimulation. Once produced, however, these cells persisted for at least 6 months. Memory cells, like killer T cells bound avidly to homologous allogeneic monolayers. There were indications that the memory T cell pool was heterogeneous. On one hand, when cells harvested 10 days after stimulation were exposed to antigen in vitro, their lytic activity increased within 24 hr but showed no further increases when the culture period was extended. In contrast, 45-day-old immune cells showed increasing lytic activity throughout a 4-day exposure to antigen. Augmentation of lytic activity in both cell populations was independent of DNA synthesis through the first 24 hr of culture. Subsequent increases in the activity of 45-day cells was dependent upon cell proliferation. Both the antigen-independent augmentation of lytic activity which followed culturing of immune cells, and the antigen-induced differentiation of memory cells were reversibly inhibited by a series of drugs which raised lymphocyte cAMP levels.

Animals↗
PubMed1975

Studies on T cell clonal expansion. I. Suppression of killer T cell production in vivo.

Adult C57BL/6 mice immunized i.p. with an allogeneic mastocytoma cell line (P815 of the DBA/2 strain) develop cytolytically active T cells. Activity peaks at 10 to 11 days and falls rapidly thereafter. We have observed an anomalous in vitro behavior of effector cell populations harvested during this decline. The lytic activity of spleen cells harvested 12 to 18 days after alloantigen was markedly augmented after culture for 24 hr at 37 degrees C. The augmented lytic activity was caused by T cells and specificity exhibited was identical to the pre-culture population. No augmentation of lytic activity occurred when cells were cultured at 4 degrees C or when they were treated with a protein synthetic inhibitor (pactamycin) at concentrations which did not compromise cytotoxic expression by the starting population. Augmentation of cytolysis was independent of DNA synthesis and did not require the presence of added antigen. When immune lymphoid cell populations were depleted of effector cells by adsorption onto allogeneic monolayers and then cultured, new killer cells differentiated within a 24-hr period. This process was not augmented by the addition of antigen to the nonadherent cell population. We interpret these demonstrations to show: i) that there is a pre-killer T cell whose differentiation into an effector cell requires de novo protein synthesis but not cell proliferation, and ii) that the in vivo fall in lytic activity during the primary immune response is at least partially caused by suppression of the differentiation of this pre-killer cell. Furthermore, we conclude that the pre-killer cell is distinct from a memory T cell because: i) its conversion to an effector cell is antigen-independent and ii) because, unlike the memory cell, pre-killers do not bind avidly to allogeneic cell monolayers.

Animals↗
PubMed2026

Shared inheritance reveals landscape of somatic and germline cancer risk in TP53.

Pathogenic variants in TP53, the key tumor suppressor gene underlying Li-Fraumeni syndrome (LFS), are among the best-established causes of inherited cancer predisposition. However, large-scale sequencing has revealed that many apparently pathogenic TP53 variants detected in blood are the result of somatic clonal expansions, complicating risk interpretation. Using blood-derived whole-exome data from 469,391 UK Biobank participants, we combined the variant allele fraction (VAF) with haplotype-sharing analysis to distinguish germline and somatic TP53 variants. Germline variants were concentrated at sites linked to partial loss of p53 function and lower disease penetrance, whereas classic LFS alleles appeared to be predominantly somatically acquired. Classic LFS alleles at high VAF conferred markedly increased risk of hematological malignancy but not solid tumors, indicating an important contribution from large TP53-mutant clonal expansions. The prevalence of somatic clonal expansion also correlated with missense variant pathogenicity, suggesting that somatic activity provides an informative in vivo proxy for functional impact. These results provide new insights into TP53-associated cancer risk at the population level, demonstrate that somatic rather than germline risk predominates in middle-aged healthy adults, and provide a scalable framework for variant classification in large-scale population genomics.

Humans↗
PubMed1977

Antigen-binding lymphocytes in guinea pigs. I.B cell expansion to the monovalent antigen L-tyrosine-p-azophenyl trimethylammonium (tyr(TMA)) in the absence of antibody production.

The monofunctional antigen L-tyrosine-p-azophenyltrimethylammonium chloride, tyr(TMA), and the polyfunctional antigen, TMA-human gamma-globulin (TMA-HGG), were used to investigate the antigen structural requirements necessary for clonal proliferation of B cells. This clonal expansion was characterized with respect to receptor immunoglobulin class and affinity maturation. Antigen-binding analysis revealed that inoculation of tyr(TMA), although only of m.w. 344, triggers clonal expansion of B lymphocytes 9-fold in the absence of any apparent antibody production. There does not appear to be any maturation with respect to antibody class since greater than 90% of the tyr(TMA)-specific B cells bear the micron receptor in the nonimmune and immune state. However, the average avidity of the B cells for this antigen increases with time after immunization. In contrast, immunization with TMA-HGG results in an 18-fold increase in B lymphocytes with significant amounts of anti-TMA antibody production. With time after immunization, both maturation of average avidity and class of Ig receptor (micron leads to gamma shift) occur. These findings indicate that the functionally T cell-specific antigen tyr(TMA) can trigger clonal B cell expansion and affinity maturation at the receptor level in the absence of detectable antibody production.

Animals↗
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↗
PubMed2026

Measurable Residual Disease and the Unresolved Biology of Leukemic Stem Cells.

Measurable residual disease (MRD) testing has transformed the management of hematologic cancers by enabling detection of residual malignant cells after therapy. Current approaches rely on qPCR and next-generation sequencing to monitor leukemia-associated somatic mutations, while multiparameter flow cytometry identifies aberrant leukemic immunophenotypes. Although these methods provide valuable prognostic and therapeutic information, MRD negativity remains an imperfect surrogate for cure. Most MRD platforms evaluate CD45+, rapidly dividing leukemic populations and fail to detect quiescent cells that may survive cytotoxic therapies which efficiently target proliferating hematopoietic cells. Relapse frequently occurs despite deep molecular remission, suggesting persistence of rare leukemic stem cells (LSCs) that are intrinsically resistant to chemotherapy and targeted therapies. The paradox of relapse despite molecular remission could be explained by the presence of very small embryonic-like stem cells (VSELs) which are pluripotent, quiescent stem cells sitting at the top of cellular hierarchy in multiple adult tissues including bone marrow. A pluripotent VSEL divides through asymmetrical cell division to give rise to two cells of different sizes and fates, smaller cell is to self-renew while the bigger is lineage-restricted and tissue-committed progenitor which undergoes extensive epigenetic changes, divides rapidly and undergoes clonal expansion before further differentiation. Dysfunctions of VSELs initiate both solid and hematologic cancers. Based on this view, somatic mutations monitored during MRD assessment possibly represent downstream consequences of clonal expansion rather than the initiating drivers of disease persistence. Thus, exclusive monitoring of somatic mutations and CD45 + leukemic populations possibly overlook rare, small-sized, CD45- VSELs that contribute to therapeutic resistance and relapse.

Humans↗
PubMed2026

Athero-oncology: Vascular smooth muscle cell tumor-like transformation in atherosclerosis and therapeutic opportunities.

Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases, and its pathogenesis and treatment strategies remain major challenges. Recent advances in single-cell RNA sequencing and lineage tracing have revealed that vascular smooth muscle cells (VSMCs) are not merely passive structural components of atherosclerotic plaques, but highly plastic participants that undergo clonal expansion, phenotypic modulation, and transdifferentiation into functionally diverse cell states. These findings have prompted the emergence of an "athero-oncology" framework, which explores selected tumor-like cellular programs in VSMCs during AS without equating atherosclerosis with cancer. In this review, we summarize the evidence supporting VSMC-derived clonal expansion and phenotypic diversification in atherosclerotic lesions and discuss key mechanisms involved in this process, including proliferative expansion and survival programs, metabolic reprogramming, epigenetic regulation, DNA damage and genomic stress, VSMC senescence, pathological angiogenesis, and remodeling of the inflammatory and immune microenvironment. We further highlight shared signaling pathways between VSMC-driven plaque remodeling and tumor biology, while emphasizing fundamental differences between AS and malignant disease in growth limitation, mutational burden, metastatic potential, and clinical behavior. Finally, we discuss oncology-inspired therapeutic opportunities and boundaries, including pathway-level targeting of proliferative, metabolic, epigenetic, and inflammatory programs, as well as the risks of directly repurposing anticancer therapies for chronic vascular disease. This framework may provide new insights into vascular biology and therapeutic development.

atherosclerosis↗
PubMed2025

A genome-wide, CRISPR-based screen reveals new requirements for translation initiation and ubiquitination in driving adipogenic fate change.

In response to excess nutrients, white adipose tissue expands by both generating new adipocytes and upregulating lipogenesis in existing adipocytes. Here, we performed a genome-wide functional CRISPR screen to identify regulators of adipogenesis in the mouse 3T3-L1 preadipocyte model. In this pooled screening strategy, we used FACS to isolate populations based on lipid content, gating for fluorescence intensity of lipophilic fluorescent BODIPY dye. Additionally, we categorized whether the gene functions primarily during mitotic clonal expansion, lipogenesis, or both. We found that translation initiation and ubiquitin-dependent protein stability regulators drive both adipogenic fate change and lipogenesis. We further supported these findings with proteomics, demonstrating that essential changes in protein reprogramming can drive or inhibit 3T3-L1 adipogenesis independent of transcription. Furthermore, we demonstrated that specific branches of the hypusination pathway, a conserved regulator of translation initiation, are critical for translating adipogenic inducers of mitotic clonal expansion and that the neddylation/ubiquitin pathway modulates insulin sensitivity during lipogenesis.

Animals↗
PubMed2026

Clonal stochasticity in early NK cell response to mouse cytomegalovirus is generated by mature subsets of varying proliferative ability.

Natural killer (NK) cells are classically defined as innate immune cells, but experiments show that mouse cytomegalovirus (MCMV) infection in C57BL/6 mice can cause NK cells to undergo antigen-specific proliferation and memory formation, similar to adaptive CD8+ T cells. One shared behavior between CD8+ T cells and NK cells is clonal expansion, where a single stimulated cell proliferates rapidly to form a diverse population of cells. For example, clones derived from single cells are most abundant during expansion when they are primarily CD27- for NK cells and CD62L- for T cells, phenotypes derived from precursor CD27+ and CD62L + cells, respectively. Here we determined the mechanistic rules involving proliferation, cell death, and differentiation of endogenous and adoptively transferred NK cells in the expansion phase of the response to MCMV infection. We found that the interplay between cell proliferation and cell death of mature CD27- NK cells and a highly proliferative CD27-Ly6C- mature subtype and intrinsic stochastic fluctuations in these processes play key roles in regulating the heterogeneity and population of the NK cell subtypes. Furthermore, we estimate rates for maturation of endogenous NK cells in homeostasis and in MCMV infection and found that only NK cell growth rates, and not differentiation rates, are appreciably increased by MCMV. Taken together, these results quantify the differences between the kinetics of NK cell antigen-specific expansion from that of CD8+T cells and unique mechanisms that give rise to the observed heterogeneity in NK cell clones generated from single NK cells in the expansion phase.

Animals↗
PubMed2026

Genomic and transcriptomic features of HBV integration in treatment-naïve, HBeAg-positive children with chronic HBV infection.

BACKGROUND: Hepatitis B virus (HBV) integration represents a major obstacle to curing HBV; however, the landscape of HBV integration and local immune response to transcriptionally active viral integration in children with chronic HBV infection remain unclear. Herein, we aimed to elucidate this landscape in this population. METHODS: Genomic analyses using a probe-based capture strategy were performed on 18 children and 28 adults with chronic HBV infection. Spatial transcriptomics (ST) was performed on 12 children from our cohort and 3 adults from a public database. FINDINGS: All patients were hepatitis B e antigen (HBeAg)-positive and treatment-naïve. Genomically, children exhibited significantly lower clonal expansion level of HBV-integrated hepatocytes than adults, despite comparable unique breakpoint counts. After adjusting for confounding variables, age was identified as an independent risk factor for total frequency of unique integration breakpoints (b = 3.22, P = 0.005). Spatially, ST revealed that spots with transcriptionally active viral integration exhibited a sparse distribution and accounted for a low proportion of all spots in children. Notably, at these spots, children showed reduced adaptive immune cells (e.g., CD8+ T cells) but increased innate components (myeloid cells, Kupffer cells, activated dendritic cells) and APC co-stimulation, whereas adults exhibited a uniform reduction of immune cell populations. INTERPRETATION: Compared with adults, children exhibit lower clonal expansion of HBV-integrated hepatocytes and distinct immune profiles in response to transcriptionally active viral integration, offering new insights into their differing clinical course. FUNDING: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education).

Humans↗
PubMed2026

Postzygotic biallelic inactivation of FDFT1 underlies solitary lesion formation in porokeratosis of Mibelli.

BACKGROUND: Porokeratosis reflects clonal expansion of keratinocytes with biallelic inactivation of mevalonate-cholesterol biosynthesis pathway genes. In disseminated porokeratosis (DP), lesions arise through independent somatic second hits in carriers of heterozygous germline pathogenic variants, whereas porokeratosis of Mibelli (PM) is usually solitary, and its molecular basis remains incompletely defined. OBJECTIVE: To elucidate the molecular basis of solitary PM. METHODS: We analyzed blood and lesional epidermis from seven patients with solitary PM within a 156-patient porokeratosis cohort using deep sequencing, copy-number/SNP profiling, and methylation analysis. RESULTS: Solitary PM plaques were larger and more irregular than the annular DP lesions. No pathogenic germline variants were detected in MVK, PMVK, MVD, FDPS, or FDFT1. Three patients had somatic biallelic genetic inactivation of FDFT1 through putative deleterious variants and/or focal microdeletions. The remaining four showed FDFT1 promoter hypermethylation with loss of heterozygosity (LOH) at the FDFT1 locus due to copy-neutral LOH or a monoallelic 8p deletion, consistent with early monoallelic epigenetic silencing, followed by genetic loss of the remaining active allele. In one patient, part of the plaque expanded centrifugally over 7.5 years. CONCLUSION: Solitary PM can be driven by postzygotic, lesion-restricted, biallelic inactivation of FDFT1 through genetic or epigenetic mechanisms within a single epidermal clone, promoting clonal expansion. This model may explain the tendency toward solitary PM lesions. The low probability of acquiring postzygotic biallelic inactivation without germline predisposition may underlie solitary PM and suggest a low recurrence risk for offspring, unlike DP driven by germline heterozygosity.

General dermatology↗
PubMed2025

SURROGATE SELECTION OVERSAMPLES EXPANDED T CELL CLONOTYPES.

Surrogate selection is an experimental design that without sequencing any DNA can restrict a sample of cells to those carrying certain genomic mutations. In immunological disease studies, this design may provide a relatively easy approach to enrich a lymphocyte sample with cells relevant to the disease response because the emergence of neutral mutations associates with the proliferation history of clonal subpopulations. A statistical analysis of clonotype sizes provides a structured, quantitative perspective on this useful property of surrogate selection. Our model specification couples within-clonotype birth-death processes with an exchangeable model across clonotypes. Beyond enrichment questions about the surrogate selection design, our framework enables a study of sampling properties of elementary sample diversity statistics; it also points to new statistics that may usefully measure the burden of somatic genomic alterations associated with clonal expansion. We examine statistical properties of immunological samples governed by the coupled model specification, and we illustrate calculations in surrogate selection studies of melanoma and in single-cell genomic studies of T cell repertoires.

Bayes’s rule↗