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Results for “clonality”

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PubMed2004

Repeated clonal relapses in classical Hodgkin's lymphoma and the occurrence of a clonally unrelated diffuse large B cell non-Hodgkin lymphoma in the same patient.

Classical Hodgkin's lymphoma (cHL) and B-cell Non-Hodgkin Lymphoma (B-NHL) occasionally occur in the same patient. However, molecular studies that aim at determining the clonal relationship between both lymphomas are rare. In most instances, the lymphoma components appear to be derived from the same germinal center (GC) B cell precursor. We describe the molecular monitoring of repeated clonal relapses in a patient with cHL in whom diffuse large B cell NHL (DLBCL) developed concurrently. Intriguingly, both lymphomas were clonally unrelated. Thus, the derivation from a shared precursor likely is not a general rule in cHL and DLBCL arising in the same patient.

Adult↗

PubMed1982

Clonal expression of the Tn antigen in erythroid and granulocyte colonies and its application to determination of the clonality of the human megakaryocyte colony assay.

To evaluate whether exposure of Tn determinants at the surface of human erythrocytes, platelets, and granulocytes could arise from a somatic mutation in a hemopoietic stem cell, burst-forming unit erythroid (BFU-E) colonies, colony-forming unit granulocyte-macrophage (CFU-GM), and colony-forming unit-eosinophil (CFU-Eo) were grown from a blood group O patient with a typical Tn syndrome displaying two distinct populations (Tn(+) and Tn(-)) of platelets, granulocytes, and erythrocytes. A large number of colonies was observed. Individual colonies were studied with a fluorescent conjugate of Helix pomatia agglutinin (HPA). A sizeable fraction of each of the erythroid and granulocytic colonies appeared to consist exclusively of either HPA-positive or HPA-negative cells, thereby demonstrating the clonal origin of those exhibiting the Tn marker. Similar results were obtained from a second patient. These findings establish that the HPA labeling of Tn cells is an accurate marker permitting assessment of the clonality of the human megakaryocyte (MK) colony assay. For the study of MK cultures a double-staining procedure using the HPA lectin and a monoclonal antiplatelet antibody (J-15) was applied in situ to identify all MK constituting a colony. Our results, obtained in studies of 133 MK colonies, provide definitive evidence that the human MK colony assay is clonal because all MK colonies were exclusively composed of Tn(+) and Tn(-) MK. Furthermore, the distribution of MK within a single colony was shown to be seminormal with a mean at 6 MK, isolated MK typically being absent in culture. Comparison of the proportion of mature Tn(+) cells in blood with their respective Tn(+) progenitors has also shown that no proliferative advantage occurs after the commitment; because Tn polyagglutinability is an acquired disorder, then the expansion of the Tn(+) clone must occur either during the proliferative stage of the pluripotent stem cell or during the commitment itself. This study therefore affords evidence that a blood group antigen plays a role in the differentiation of a pluripotent stem cell.

Adult↗

PubMed1988

Studies on the clonality of the response to an epitope of a protein antigen. Randomness of activation of epitope-recognizing clones and the development of clonal dominance.

Syngeneic mice immunized with tobacco mosaic virus protein (TMVP) can differ with respect to their ability to produce antibodies that bind a decapeptide epitope representing residues 103 to 112 of TMVP, and with respect to the fine specificity of the decapeptide binding antibodies as determined by their ability to bind several synthetic analogues of the decapeptide. To elucidate the mechanism responsible for the differences between the syngeneic animals in their ability to make anti-decapeptide antibodies, spleen cells from a large number of naive CSW mice were pooled, and aliquots were transferred (either including or excluding resident T cells) into naive recipients that were subsequently immunized with TMVP. Examination of the frequency and fine specificity of anti-decapeptide antibodies revealed that the recipients exhibited various clonalities of decapeptide binding antibody responses similar to those seen in a normal population of CSW mice. Moreover, the response of each individual mouse was of a restricted clonality despite the availability of a more extensive repertoire of decapeptide-recognizing clones. The results indicate that the selection of the clonality of the antibody response was not determined by the presence (or absence) of particular clones of B or T cells and that the mechanism responsible for generating differences between mice must have acted, subsequent to introduction of the Ag, by activation of a limited number of clones randomly selected by Ag and/or by Ag-driven mutation. The long term nature of the antibody response to the decapeptide epitope was also investigated. The response was shown to be "locked-in" for the life of the immunized individual. Thus, individuals that responded to TMVP but that did not produce antibodies to the decapeptide after the first set of immunizations with TMVP maintained their non-responsiveness to the decapeptide after the second set of immunizations with the protein. However, individuals that responded to an initial set of immunizations with TMVP by producing antibodies to the decapeptide epitope continue to produce antibodies to the decapeptide after a second set of immunizations with TMVP. The fine specificity of the decapeptide-binding antibodies also appeared to be "locked in" throughout the life of the immunized individual. The long term maintenance of the clonability of the antibody response does not appear to be influenced by Ag-specific T cells and is strictly a function of memory B cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1985

Activation through CD3 molecule leads to clonal expansion of all human peripheral blood T lymphocytes: functional analysis of clonally expanded cells.

Monoclonal antibodies directed against CD3, a T cell-specific surface molecule essentially required for activation of these cells, are highly mitogenic for resting human peripheral blood T lymphocytes. A predetermined optimal concentration of anti-CD3 monoclonal antibody WT32 was employed to activate T cells cultured in limiting-dilution microcultures containing irradiated feeder cells and exogeneous interleukin 2. Frequencies of cells triggered into clonal expansion by WT32 under these culture conditions were 0.57 to 0.72 and 0.90 to 1.10 in peripheral blood mononuclear cells and E rosette-positive cells, respectively. It appeared that WT32 could induce virtually every human peripheral blood T lymphocyte to expand into a clonal progeny of 5 to 40 X 10(4) cells in 14 to 18 days of culture. This progeny was tested for cytolytic effector function with 51Cr-labeled murine P815 targets in the presence of PHA to detect all cytotoxic T lymphocytes (CTL) regardless of specificity, and was also assayed for natural killer like activity against K562 target cells. Frequencies of cells in the human peripheral blood T cell compartment giving rise to a clonal progeny expressing CTL function was 1/3, whereas 1/6 to 1/5 expanded into effector cell populations possessing NK activity. Frequency analysis of CD4-positive and CD8-positive populations, activated by WT32 in limiting dilution microcultures, demonstrated that 1 to 6% of the CD4-positive and 100% of the CD8-positive peripheral blood T lymphocytes expanded into CTL.

Antibodies, Monoclonal↗

PubMed1997

Clonal HTLV-I-infected CD4+ T-lymphocytes and non-clonal non-HTLV-I-infected giant cells in incipient ATLL with Hodgkin-like histologic features.

Lymph nodes from the incipient or early neoplastic phase of adult T-cell leukemia/lymphoma (ATLL) histologically resemble Hodgkin's disease. Integrated proviral human T-lymphotrophic virus type I (HTLV-I) has been demonstrated in such lesions. We studied 18 patients with this disease, and about half of the cases developed typical ATLL within 2 or 3 years. In all cases, either mono- or oligoclonal cell populations with proviral HTLV-I DNA were detected by Southern blot analysis and/or inverse polymerase chain reaction (IPCR). In addition, either a mono- or oligoclonal rearrangement of T-cell receptor genes was demonstrated. Giant cells with Reed-Sternberg-like histological features revealed CD15 and CD30 positivity. The background infiltrating lymphocytes represented either no or only minimal nuclear abnormalities with a CD4+ T-cell phenotype. In less than half of all cases, Epstein-Barr virus (EBV) infected the giant cells. A mixed EBV-A and -B type was found in 3, and a multiple genotype of EBV lymphocyte-determined membrane antigen (LYDMA) was found in 6 cases. These results could have been due to the immunodeficient status of the patients. A single-cell PCR of the giant cell, B cell, CD4+ or CD8+ T cells could be performed after cell sorting in 4 cases. HTLV-I infection was frequently found in the CD4+ T cells, but in neither the giant cells nor the B cells. The CD4+ T cells exhibited clonality. The giant cells showed various PCR products of IgH, and also expressed recombination activating genes (RAG). In summary, the giant cells were reactive cells, which resembled the immature B-lineage cells, while HTLV-I infected the CD4+ T cells, which demonstrated clonality. Based on these above findings, we consider CD4+ cells to play an important role in ATLL tumorigenesis.

Adolescent↗

PubMed2002

Molecular evidence of a common clonal origin and subsequent divergent clonal evolution in vulval intraepithelial neoplasia, vulval squamous cell carcinoma and lymph node metastases.

VIN is thought to be the precursor of some VSCCs because it is monoclonal, frequently occurs contiguously with VSCC and shares similar risk factors with a subgroup of VSCC. There has been no conclusive molecular evidence supporting this assumption. We performed X-chromosome inactivation analysis on 9 cases of lone VIN, 10 cases of VSCC and associated contiguous VIN and 11 cases of VSCC and associated noncontiguous VIN. Eight of the 9 cases of lone VIN appeared to be monoclonal. All 7 informative and monoclonal cases of VIN with contiguous VSCC and 6/9 informative cases of VIN with noncontiguous VSCC showed patterns of X-chromosome inactivation consistent with a common monoclonal origin for both VIN and VSCC. Two of the 9 cases of VIN with noncontiguous VSCC showed X-chromosome inactivation patterns consistent with a separate clonal origin. We performed LOH analysis at 6 chromosomal loci on these samples and 7 cases with lymph node metastases. Identical losses occurred 7 times in VIN and contiguous VSCC (random probability 1.2 x 10(-9)), twice in VIN and noncontiguous VSCC (random probability 1.5 x 10(-3)) and 3 times in VSCC and associated metastases (random probability 1.8 x 10(-5)). Some losses occurring in VSCC did not appear in the contiguous VIN or associated metastases and vice versa. These data provide molecular evidence that VIN is the precursor of VIN-associated VSCC, that multifocal disease may arise via either different clones or a single clone and that continued divergent clonal evolution may occur in vulval neoplasia.

Carcinoma, Squamous Cell↗

PubMed1994

Clonal analysis in the chicken retina reveals tangential dispersion of clonally related cells.

Development of the chicken retina was investigated through clonal analysis using retroviral vectors. Replication-incompetent retroviral vectors encoding either human placental alkaline phosphatase, beta-galactosidase, or a viral core protein were used in paired combinations to infect retinal progenitor cells from Embryonic Days 2.5-7.0. Labeled clones were analyzed late in embryonic development after retinal histogenesis was complete. The early accessibility of the chicken retina, combined with its large final size, resulted in the labeling of much larger clones than had been reported previously in other species. The clones were composed of many cell types, supporting previous conclusions from other vertebrates that the progenitor cells of developing retina are multipotent. The majority of clones derived from early infections consisted of multiple tightly clustered arrays of cells accompanied by dispersed individual cells. Clonal complexity and tangential dispersion were greater in peripheral than central retina and decreased considerably with increasing age of infection. These observations suggest that early during retinal development, shortly after optic cup formation, there is considerable mixing of progenitor cells.

Animals↗

PubMed1990

Intercellular bridges between germ cells in the immature golden hamster testis: evidence for clonal and non-clonal mode of proliferation.

Intercellular bridges of prespermatogonia and of the first A-spermatogonia in the maturing testes of newborn to 17-day-old golden hamsters have been studied by electron microscopy. Incomplete cytokinesis of dividing M- and T2-prespermatogonia and A-spermatogonia produces these bridges, which undergo different developmental fates. Bridges of the first A-spermatogonia are stable beyond subsequent mitoses of these cells; this gradually leads to the formation of bridge-connected groups of synchronously developing germ cells. Thus, the clonal mode of male germ cell proliferation is already established in this period of testis maturation. During mitoses, pre-existing bridges reversibly develop structural modifications, i.e., considerable elongation and formation of a bridge-partitioning complex. In contrast, intercellular bridges of prespermatogonia are mostly severed and become lost during subsequent mitoses of the cells involved; this results in separation of the germ cells and represents a mainly non-clonal mode of M- and T2-prespermatogonial proliferation. Here, too, pre-existing bridges elongate and develop the bridge-partitioning complex during subsequent mitoses of the joined cells, but this is superposed and interrupted by the simultaneous process of disconnection of the bridges.

Animals↗

PubMed1990

Failure of clonal deletion in neonatally thymectomized mice: tolerance is preserved through clonal anergy.

Self-tolerance is achieved in part through intrathymic deletion of self-reactive T cells. The necessity of the thymus for this process is suggested by the development of autoimmune diseases in neonatally thymectomized (neoTx) mice and by the failure of clonal deletion in nude mice. Indeed, the present study demonstrates that neonatal thymectomy on day 3 after birth results in the failure of clonal deletion of V beta 11+ T cells in BALB/c mice and V beta 5+ and V beta 6+ T cells in DBA/2 mice. However, these potentially autoreactive cells are nonfunctional as measured by proliferation and lymphokine production after stimulation with appropriate anti-V beta mAbs or stimulator cells. It appears that this induction of nonresponsiveness may have occurred extrathymically: the early neonatal thymus (presumably the source of the peripheral T cells observed in neoTx mice) also contains T cells with self-reactive receptors, but these cells are fully functional. Therefore, neonatal thymectomy aborts deletion of self-reactive T cells, but self-tolerance is maintained through functional inactivation of potentially self-reactive clones.

Animals↗

PubMed1990

Distinct fates of self-specific T cells developing in irradiation bone marrow chimeras: clonal deletion, clonal anergy, or in vitro responsiveness to self-Mls-1a controlled by hemopoietic cells in the thymus.

Elimination of potentially self-reactive T lymphocytes during their maturation in the thymus has been shown to be a major mechanism in accomplishing self-tolerance. Previous reports demonstrated that clonal deletion of self-Mls-1a-specific V beta 6+ T lymphocyte is controlled by a radiosensitive I-E+ thymic component. Irradiation chimeras reconstituted with I-E- bone marrow showed substantial numbers of mature V beta 6+ T cells despite host Mls-1a expression. Analysis of the functional properties of such chimeric T cells revealed a surprising variability in their in vitro reactivity to host Mls-1a, depending on the H-2 haplotype of stem cells used for reconstitution. In chimeras reconstituted with B10.S (H-2s) stem cells, mature V beta 6+ lymphocytes were present but functionally anergic to host-type Mls-1a in vitro. In contrast, in chimeras reconstituted with B10.G (H-2q) bone marrow, nondeleted V beta 6+ cells were highly responsive to Mls-1a in vitro. These findings suggest that clonal anergy of V beta 6+ cells to self-Mls-1a may be controlled by the affinity/avidity of T cell receptor interactions with bone marrow-derived cells in the thymus depending on the major histocompatibility complex class II molecules involved. Furthermore, chimeras bearing host (Mls-1a)-reactive V beta 6+ cells did not differ clinically from those with anergic or deleted V beta 6+ cells and survived more than one year without signs of autoimmune disease. Interestingly, their spleen cells had no Mls-1a stimulatory capacity in vitro. Therefore, regulation at the level of antigen presentation may be an alternative mechanism for maintenance of tolerance to certain self-antigens such as Mls-1a.

Animals↗

PubMed2000

Clonal proliferation of B lymphocytes in the germinal centers of human reactive lymph nodes: possibility of overdiagnosis of B cell clonal proliferation.

Clonal expansion of the germinal center B cells of human reactive lymph nodes was analyzed. By micromanipulation, 28 germinal centers were microdissected from three nonneoplastic lymph nodes that had been fixed with formalin. Immunoglobulin heavy chain variable (V) region gene rearrangement was examined by seminested polymerase chain reaction (PCR) using two sets of primers (FR2-J and FR3A-J). An oligoclonal development (one to five clones) was found in each germinal center. Depending on the primer used, four or five (16%) of the germinal centers showed a single rearrangement band. The average number of B-cell clones in each germinal center was approximately 2.5. Next, the authors analyzed 50 endoscopic biopsy specimens from 6 patients with non-mucosa-associated lymphoid tissue (MALT) type gastric lymphoma, 25 patients with chronic gastritis, and 19 patients with nonspecific colitis. In addition to the samples from the 6 patients with malignant lymphoma, 8 of 44 biopsy samples (18.2%) from patients diagnosed as having chronic gastritis or nonspecific colitis showed one or two amplified bands. These results indicate that PCR analysis of immunoglobulin heavy chain V region gene rearrangement in small biopsy specimens could be misleading, causing overdiagnosis of reactive lymphoid tissue as B-cell clonal proliferation.

Adenocarcinoma↗

PubMed1990

Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance.

During development in the thymus, T cells are rendered tolerant to self antigens. It is now apparent that thymocytes bearing self-reactive T cell receptors can be tolerized by processes that result in physical elimination (clonal deletion) or functional inactivation (clonal anergy). As these mechanisms have important clinical implications for transplantation and autoimmunity, current investigations are focused on understanding the cellular and molecular interactions that generate these forms of tolerance.

Animals↗

PubMed2006

Clonal and non-clonal chromosome aberrations and genome variation and aberration.

The theoretical view that genome aberrations rather than gene mutations cause a majority of cancers has gained increasing support from recent experimental data. Genetic aberration at the chromosome level is a key aspect of genome aberration and the systematic definition of chromosomal aberrations with their impact on genome variation and cancer genome evolution is of great importance. However, traditionally, efforts have focused on recurrent clonal chromosome aberrations (CCAs). The significance of stochastic non-clonal chromosome aberrations (NCCAs) is discussed in this paper with emphasis on the simple types of NCCAs that have until recently been considered "non-significant background". Comparison of various subtypes of transitional and late-stage CCAs with simple and complex types of NCCAs has uncovered a dynamic relationship among NCCAs, CCAs, overall genomic instability, and karyotypic evolution, as well as the stochastic nature of cancer evolution. Here, we review concepts and methodologies to measure NCCAs and discuss the possible causative mechanism and consequences of NCCAs. This study raises challenging questions regarding the concept of cancer evolution driven by stochastic chromosomal aberration mediated genome irregularities that could have repercussions reaching far beyond cancer and organismal genomes.

Chromosome Aberrations↗

PubMed2003

Thyroid gland clonality revisited: the embryonal patch size of the normal human thyroid gland is very large, suggesting X-chromosome inactivation tumor clonality studies of thyroid tumors have to be interpreted with caution.

It is widely assumed thyroid carcinomas, adenomas, and many hyperplastic nodules are monoclonal. This belief is based on X-chromosome inactivation analyses of thyroid tumors. However, X-chromosome inactivation studies of tumors are informative only when interpreted in the context of the clonal composition of the surrounding normal tissue, and in the case of thyroid tissue, such analyses have never been systematically performed in humans. The aim of this study was to determine the embryonal patch size of the human thyroid gland. We performed human androgen receptor (HUMARA) assay-based X-chromosome inactivation analysis on 20 microdissected normal thyroid specimens from 16 female subjects. Monoclonality was observed in 70% of tested specimens, and polyclonal X-inactivation patterns were present in only 30% of specimens. According to our results the monoclonal patch size of normal human thyroid tissue is between 48 mm(2) and 128 mm(2) (1-4 x 10(5) thyrocytes). Our data indicate that normal thyroid epithelium is organized into large stem cell-derived monoclonal patches. Therefore, monoclonality in neoplastic and hyperplastic lesions may just be a reflection of normal thyroid epithelium clonal composition.

Adult↗

PubMed1999

[Is the a connection between prolonged carriage and clonal hospital-to-hospital clonal spread of multiresistant Pseudomonas aeruginosa of the O12 serotype? Are the specific habits of the hospitals involved the cause?].

Results obtained using our expert computer program (SIR, 12A, Montpellier, France) over the last seven years (1991-1998) suggest that the increased incidence of superficial pus infection or colonization with O12 Pseudomonas aeruginosa, together with the significantly longer carriage duration for this organism as compared to non O12. P. aeruginosa, may contribute to the current endemic clonal spread of O12 P. aeruginosa in a general hospital in Rodez, France, and in neighboring extended-care facilities. This ecological observation may reflect poor compliance with basic hygiene procedures in the Rodez hospital and in neighboring hospitals. The O12 P. aeruginosa clone in the Rodez hospital is indistinguishable from the one that has disseminated throughout Europe, suggesting that the ecological observation and hypothesis described herein may deserve to be investigated in other institutions that are also the site of endemic clonal O12 P. aeruginosa dissemination.

Disease Outbreaks↗

PubMed1992

Persistent clonal areas and clonal expansion in Barrett's esophagus.

Three patients with Barrett's esophagus who had cytogenetic abnormalities detected in their metaplastic epithelium developed high-grade dysplasia or adenocarcinoma during prospective surveillance over a period of 1.5 to 6 years. In the 3 cases, cytogenetic abnormalities that were associated with the most advanced histological lesions were present in samples obtained 11, 25, and 48 months prior to the diagnosis of high-grade dysplasia or carcinoma. In a fourth patient, marker chromosomes found in a Barrett's adenocarcinoma were also present in an esophageal region spatially removed from the tumor. In all four patients, clonal cytogenetic abnormalities were present in samples obtained at widespread locations in the Barrett's segment. These observations suggest that in some patients with Barrett's esophagus clonal proliferations arise in regions of benign histology and spread to involve large areas of Barrett's mucosa. These clones persisted when the disease progressed to high-grade dysplasia or adenocarcinoma.

Adenocarcinoma↗

PubMed1991

Intrathymic induction of neonatal tolerance to Mls-1a determinant: clonal deletion and clonal anergy by haematolymphoid cells.

Newborn BALB/c (Mls-1b) mice were intravenously injected with either bone marrow cells (BMC) or peritoneal exudate cells (PEC) from Mls semi-allogeneic (BALB/c x AKR)F1 mice. Thymic cells of these mice, obtained 7 days after the injection, were found to be unresponsive to the superantigen Mls-1a, as determined by graft-versus-host reactivity. On Day 7, deletion of T cells expressing the V beta 6 element at high levels (V beta 6hi) was observed in thymic cells of mice receiving PEC. In mice given BMC, it took 2 weeks until the proportion of V beta 6hi T cells began to decline, and a longer period was required for complete disappearance of V beta 6hi T cells. These results may indicate that although both BMC and PEC contain cells mediating tolerance, a component(s) of cells responsible for clonal deletion is deficient in BMC. Immunohistological investigation showed that on Day 7 donor type B cells were present in the thymus of mice that received PEC but absent from mice that received BMC, whereas cells expressing donor type class I as well as class II antigens were seen in both recipients. The presence of donor type B cells could be observed 8 weeks after injection of BMC. By this time, the deletion of V beta 6hi T cells was completed. These results indicate, collectively, that the tolerance of both anergy type and deletion type occurs in the naturally developing thymus, and suggest that the presence of B cells in the thymus might be required for clonal deletion.

Animals↗

PubMed1984

Clonal endurance and clonal burst size: novel indices of helper T cell heterogeneity.

This report presents a method for examining the behavior of individual antigen-responsive helper T cell precursors (pHTL), following their repeated encounter with antigen. In our model system, lymph node cells from mice immunized with keyhole limpet hemocyanin (KLH) are cultured in vitro under limiting dilution conditions, using responder cell doses chosen to ensure that each culture well contains, at the outset, at most a single KLH-reactive helper T cell precursor. Those wells which in fact did receive a KLH-reactive pHTL are identified by the accumulation of the helper T cell product, interleukin 3 (IL3), during a 6-day culture interval. The lymphocytes generated during this culture interval are washed, divided into replicate aliquots, and then further cultured (with and without additional KLH) to see if the original pHTL has generated cells which are capable of further lymphokine production. Using this approach, we found a surprising amount of variation from clone to clone in two measurements. Clones differed greatly in "endurance", that is in the ability of progeny cells to continue to secrete IL3 in the absence of additional antigenic stimulation. Among 148 clones tested, 90 were found not to continue lymphokine secretion in antigen-free secondary cultures, while IL3 production among the other 58 clones varied from 1 to 128 arbitrary units. Individual clones also varied greatly with respect to their ability to secrete additional IL3 in response to additional antigen, and in "burst size", that is in the number of new, antigen-responsive helper cell precursors which they can generate during the initial culture interval; 43% of the clones produced no new pHTL, while others produced as many as 800 new pHTL cells in an 8-day period. Neither measure correlates strongly with the amount of lymphokine originally produced by the initial "parental" pHTL. This method will allow us to examine the factors which influence the allocation of clonal progeny cells into lymphokine producing effectors and antigen-sensitive "memory" T cells.

Animals↗