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Results for “Clonal Evolution”

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PubMed1990

Analysis of clonal evolution in a tumor consisting of pSV2neo-transfected mouse fibrosarcoma clones.

The process of clonal evolution was analyzed in a line of methylcholanthrene-induced mouse fibrosarcomas. The tumor cells were transfected with pSV2neo gene and 22 clones were randomly isolated. Genetically tagged clones were mixed and inoculated into syngeneic mice. Southern blot analysis revealed that one of the clones, no. 11, dominated both in tumors in situ and in lung metastatic nodules. No. 11 clone and other clones were similar in growth rates in vitro and in vivo, in spontaneous and experimental metastatic abilities, in immunogenicity, and in the capacity of intercellular communication in vitro. Although no. 11 clone overgrew other clones in vivo, this was not the case when clones were mixed and maintained in vitro. We conclude that clonal interactions in vivo may be responsible for the dominance of no. 11 clone in the tumor. It is likely that the preferential metastasis of no. 11 clone to the lung may be a simple reflection of the proliferative advantage of the dominant clone in the tumor in situ.

Animals↗

PubMed2001

Clonal evolution in Waldenstrom macroglobulinemia highlights functional role of B-cell receptor.

The course of clonal evolution of 2 related clones in the blood of a patient with Waldenstrom macroglobulinemia (WM) indicates the functional importance for the expression of the B-cell receptor for the survival of these malignant cells. Protein and nucleotide sequencing of the paraproteins' variable regions revealed 2 predominant Vlambda and 2 VH sequences, each set comprised in the ratio 1:1.5. The 2 VH sequences and 2 Vlambda sequences shared the same VDJ and VJ junctional sequences, respectively, indicating that 2 malignant clones had evolved from a common ancestor. This is the first report on intraclonal heterogeneity in WM. Comparison of the Vlambda and VH sequences with the closest matching known germline genes showed that they contained approximately 10 somatic mutations each. The distribution and type of mutations demonstrate that mutations have continued to accumulate in the malignant clones and that selection has been operating to preserve immunoglobulin structure.

Base Sequence↗

PubMed1997

Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer.

To understand the genetic basis and clonal evolution underlying metastatic progression of human breast cancer in vivo, we analyzed the genetic composition of 29 primary breast carcinomas and their paired asynchronous metastases by comparative genomic hybridization and fluorescence in situ hybridization. The mean number of genetic changes by comparative genomic hybridization was 8.7 +/- 5.3 in primary tumors and 9.0 +/- 5.7 in their metastases. Although most of the genetic changes occurred equally often in the two groups, gains of the Xq12-q22 region were enriched in the metastases. According to a statistical analysis of shared genetic changes and breakpoints in paired specimens, 20 of the metastases (69%) showed a high degree of clonal relationship with the corresponding primary tumor, whereas the genetic composition of 9 metastases (31%) differed almost completely from that of the paired primary tumors. In both groups, however, chromosome X inactivation patterns suggested that the metastatic lesions originated from the same clone as the primary tumor. Fluorescence in situ hybridization analysis with probes specific to metastatic clones usually failed to find such cells in the primary tumor sample. In conclusion, detailed characterization of the in vivo progression pathways of metastatic breast cancer indicates that a linear progression model is unlikely to account for the progression of primary tumors to metastases. An early stem line clone apparently evolves independently in the primary tumor and its metastasis, eventually leading to multiple, genetically almost completely different, clones in the various tumor locations in a given patient. The resulting heterogeneity of metastatic breast cancer may underlie its poor responsiveness to therapy and explain why biomarkers of prognosis or therapy responsiveness measured exclusively from primary tumors give a restricted view of the biological properties of metastatic breast cancer.

Adenocarcinoma↗

PubMed1996

Clonal evolution of immunoglobulin heavy chain rearrangements in childhood B-precursor acute lymphoblastic leukemia after engraftment in SCID mice.

We grafted childhood B-precursor acute lymphoblastic leukemia (ALL) bone marrow (BM) cells into mice with severe combined immunodeficiency (SCID), in order to study the clonal evolution of immunoglobulin heavy chain (IgH) rearrangements in the absence of selective pressure by chemotherapy. BM cells from nine patients (six diagnosis samples and three relapse samples) were intravenously injected into SCID mice (three mice for each patient). All mice injected with cells from four patients developed a leukemia-like illness 12-40 weeks after injection. By PCR, new subclones that were the result of ongoing IgH rearrangement according to the mechanism operative in the injected cell populations (VH-replacement or VH to D-JH joining) were detected in the engrafted cell populations for all four patients. Subclones were mouse-specific, suggesting that subclone formation is a continuous process. Southern analysis after engraftment was unaltered as compared to the injected cells for one patient and revealed changes indicative of altered clonal composition for three patients. For two patients the observed changes possibly reflect the initial engraftment of a limited number of cells and occurred without changes in other parameters of the engrafted cell population, such as time needed for the development of leukemia, macroscopic organ involvement, immunophenotype and S-phase fraction. In one patient, we demonstrated the selective outgrowth of only a single cell type present at diagnosis, as characterized by IgH rearrangements. Our data show that evolution of clonal IgH rearrangements in B-precursor ALL may occur without the selective pressure of chemotherapy. Additionally, in some patients subclones present at diagnosis, as defined by IgH rearrangements, also possess different biological properties.

Animals↗

PubMed2026

Multiomic study of cutaneous T-cell lymphoma reveals single-cell clonal evolution in progression and therapy resistance.

Cutaneous T-cell lymphoma (CTCL) remains a challenging disease due to its significant heterogeneity, therapy resistance, and relentless progression. Multiomics technologies offer the potential to provide uniquely precise views of disease progression and response to therapy. Here, we present a comprehensive multiomics view of CTCL clonal evolution, incorporating exome, whole-genome, epigenome, bulk, single-cell T-cell receptor, and single-cell RNA sequencing of 99 clinically annotated serial skin, peripheral blood, and lymph node samples from 34 patients with CTCL. We leveraged this extensive data set to define the molecular underpinnings of CTCL progression in individual patients at single-cell resolution with the goal of identifying clinically useful biomarkers and therapeutic targets. Our studies identified recurrent progression-associated clonal genomic alterations; we highlight mutation of CCR4, phosphoinositide 3-kinase inhibitor signaling, and programmed cell death protein 1 (PD-1) checkpoint pathways as evasion tactics deployed by malignant T cells. We identified a gain-of-function mutation in STAT3 (D661Y) and demonstrated, using cleavage under targets and release using nuclease (CUT&RUN) and RNA sequencing, that it enhances binding to and transcription of genes in Rho GTPase pathways. With our previous work implicating this pathway in histone deacetylase inhibitor-resistant CTCL, these data provide further support for a previously unrecognized role for Rho GTPase pathway dysregulation in CTCL progression. Recurrent progression-associated mutations were common in the epigenetic modifier EZH2, suggesting that EZH2 inhibition may benefit patients with CTCL. Our findings support an approach in which genomic analysis is widely used for improved disease monitoring, biomarker-informed clinical trial design, and genome-guided therapeutic decision-making. Moreover, these molecular changes present new opportunities for therapeutic targeting in this challenging and incurable cancer.

Multiomics↗

PubMed1999

Clonal evolution of aplastic anaemia to myelodysplasia/acute myeloid leukaemia and paroxysmal nocturnal haemoglobinuria.

Aplastic anaemia (AA) is a non-malignant haemopoietic disorder characterised by peripheral blood pancytopenia and a hypocellular bone marrow. Successful management of acquired AA including treatment with immunosuppressive agents, mainly antithymocyte globulin (ATG) and cyclosporin or allogeneic haemopoietic stem cell transplantation, has resulted in long-term survival of many patients. The later evolution of complicating clonal disorders such as paroxysmal nocturnal haemoglobinuria, myelodysplasia and acute myeloid leukaemia in patients treated with immunosuppressive therapy may be a manifestation of the natural history of the aplasia, the development of which may or may not be increased by immunosuppressive therapy. A persistent, profound deficiency and/or defect in the stem cell compartment, despite haematological recovery after immunosuppressive therapy, may create an unstable situation which predisposes to later clonal disorders. A review of the progression of AA to clonal disorders is now outlined.

Acute Disease↗

PubMed1992

Clonal evolution of a follicular lymphoma: evidence for antigen selection.

The potential role antigens play in growth stimulation or in clonal selection of follicular lymphomas is unknown. To study this issue, we sequenced the immunoglobulin heavy chain variable region genes expressed by a follicular lymphoma from multiple biopsy specimens and also cloned and sequenced the corresponding germ-line variable gene from this patient. Comparison to the germ-line gene revealed numerous nucleotide substitutions in all of the lymphoma variable gene sequences. Some of the substitutions may have occurred in the nonmalignant precursor B cell that gave rise to this lymphoma because they were shared among all of the variable genes, but many of the mutations accumulated as the malignant clone expanded. The mutations were distributed in such a way that strongly suggested the majority of tumor cells had been positively selected through their antigen receptor. This was especially evident for the mutations that developed late in the clonal evolution of this lymphoma. These findings indicate that antigen stimulation may be involved in the growth of follicular lymphoma tumors.

Antigens, Neoplasm↗

PubMed1992

Juvenile chronic myelocytic leukemia with unusual cytogenetic clonal evolution.

Cytogenetic studies are reported in a case of juvenile chronic myelocytic leukemia with dysmyelopoiesis and skin involvement. The clonal evolution of a 6q-anomaly is described. Hematological and cytogenetic findings suggest a role of hematopoietic stem cell in this patient for whom the outcome was fatal.

Child, Preschool↗

PubMed1999

Clonal evolution as judged by immunoglobulin heavy chain gene rearrangements in relapsing precursor-B acute lymphoblastic leukemia.

Oligoclonality and ongoing clonal evolution are common features in patients with precursor-B (pre-B) acute lymphoblastic leukemia (ALL), as judged by immunoglobulin heavy chain (IgH) gene rearrangement analysis. These features are considered to be results of secondary rearrangements after malignant transformation or emergence of new tumor clones. In the present study we analyzed the IgH gene rearrangement status in 18 cases with relapsing pre-B ALL using variable heavy chain (V(H)) gene family specific polymerase chain reaction (PCR) amplification and single stranded conformation polymorphism (SSCP) analysis. Clonal IgH rearrangements were displayed in all leukemias but one, and altered rearrangement patterns occurred in five cases (29%), which were selected for detailed nucleotide sequence analysis. In one case, multiple subclones at diagnosis were suggested to be derived from a progenitor clone through joining of different V(H) germline gene segments to a pre-existing D-J(H) complex (V(H) to D-J(H) joining). Evidence for V(H) gene replacement with identical N-sequences at the V(H)-D junction and a common D-J(H) region was observed in one case. Diversification at the V(H)-D junction consisting of heterogeneous N-sequences were observed in one case. This molecular modification of the V(H)-D region could fit a hypothesized "open-and-shut" mechanism. Nevertheless, despite these ongoing events at least one IgH rearrangement remained unchanged throughout the disease in most patients, indicating that the immunoglobulin heavy chain locus can be a suitable marker for detection of minimal residual disease (MRD).

Base Sequence↗

PubMed2026

GATA2 deficiency: enhancer deregulation, immune surveillance failure, and clonal evolution.

Germline mutations in GATA2 cause a syndromic inborn error of immunity characterized by cytopenia, infections, immune dysregulation, and a marked predisposition to myelodysplastic syndrome and acute myeloid leukemia. Initially defined by the DCML phenotype-dendritic cell, monocyte, B- and NK-cell deficiency-GATA2 deficiency is now recognized as a disorder of global immune-hematopoietic homeostasis. Recent multi-omics and experimental models reveal enhancer-driven inflammatory rewiring, IRF8-dependent lineage imbalance, and premature hematopoietic aging. In parallel, adaptive immune defects, including impaired B- and T-cell development and function, contribute to defective immune surveillance. These alterations not only explain susceptibility to infection but also shape clonal evolution and malignant transformation. Clinically, improved risk stratification and transplant outcomes underscore the importance of early recognition and monitoring of immune dysfunction. GATA2 deficiency thus represents a paradigm linking immune dysregulation, inflammatory stress, and cancer predisposition.

Humans↗

PubMed1983

Clonal evolution in a human neuroblastoma.

Tumor samples, obtained from a single patient at two points in his illness, have enabled us to study clonal evolution in a neuroblastoma. Cells from the primary tumor demonstrated considerable heterogeneity in terms of chromosome number; cells from 4 subsequent metastases were all nearly diploid; and cells from a tumor produced in a mouse by the injection of cells from the primary tumor were hypotriploid in modal number. All of the tumor samples contained the same marker chromosome rearrangements, indicating their origin from a common precursor. Each of the cell lines analyzed (including those from the patient's metastases, those from the tumor in a mouse, and those from the primary tumor after 11 months in continuous culture) also contained different and distinguishing chromosome abnormalities. The differences in karyotype among these tumor samples and cell lines presumably reflect the different selection pressures at work in each instance.

Abdominal Neoplasms↗

PubMed2005

[Clonal evolution of abnormal Philadelphia chromosome-negative cells after imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia].

OBJECTIVE: To investigate clonal evolution of abnormal Philadelphia chromosome-negative cells (Ph- CE) after imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML). METHODS: Bone marrow cells G-banding karyotype was evaluated every 3 months in 100 patients with Ph+ CML after achieving hematologic responses on the course of imatinib therapy. There were 54 patients in chronic phase (CP), 37 in accelerated phase (AP) and 9 in blast phase (BP). RESULTS: After a median follow-up of 32 months (ranged 25-34 months), 11 patients, including 5 cases in CP, 5 in AP and 1 in BP, developed transient, interrupted or continuous Ph- CE after 3 - 29 months on imatinib therapy. Ph- CE emerged at the beginning of Ph+ cells decreasing or after Ph+ cells disappearing. The proportion of Ph- CE, was negatively correlated with the proportion of Ph+ cells (P < 0.05). Ph- CE commonly included +8 (45.5%) and +Y (27.3%). Five patients had additional cytogenetic abnormalities besides Ph+ in Ph- CE. Seven of the patients with Ph- CE achieved a major cytogenetic response while 9 of them achieved a complete hematologic response. One patient with Ph- CE in AP progressed to BP 20 months after the initiation of the therapy while the rests remained in hematologic or cytogenetic responses. CONCLUSION: Ph- CE occurred in about 11% of the patients with Ph+ CML who achieved major or minor cytogenetic responses on imatinib therapy. After a median follow-up of more than 2 years, most of the patients with Ph- CE were in a stable status with no disease progression.

Adult↗

PubMed2001

Clonal evolution and progression of 20-methylcholanthrene-induced squamous cell carcinoma of mouse epidermis as revealed by DNA instability and other malignancy markers.

We examined the clonal evolution of skin malignant lesions by repeated topical applications of 20-methylcholanthrene (20-MC) to the skin, which induces hyperplastic epidermis, papillomatous lesion and invasive carcinoma in mice. The lesions were examined histologically and immunohistochemically with anti-single-stranded DNA after acid hydrolysis (DNA-instability test), p53, VEGF, DFF45, PCNA and AgNORs parameters analyses. Multiple clones with increased DNA instability comparable to that of invasive carcinoma were noted in early-stage (2-6 weeks) hyperplastic epidermis, and their number increased in middle (7-11 weeks), and late-stages (12-25 weeks) of hyperplastic epidermis, indicating that they belong to the malignancy category. All papillomatous lesions and invasive carcinomas showed a positive DNA-instability test. Positive immunostaining for various biomarkers and AgNORs parameters appeared in clones with a positive DNA-instability test in early-or middle-stage hyperplastic epidermis, and markedly increased in late-stage hyperplastic epidermis, papillomatous lesions and invasive carcinomas. The percentage of PCNA-positive vascular endothelial cells was significantly higher in VEGF-positive lesions with a positive DNA-instability test and became higher toward the late-stage of progression. Cut-woundings were made to papillomatous and invasive carcinoma lesions, and the regeneration activity of vascular endothelial cells was determined by using flash labeling with tritiated thymidine (3H-TdR). In small papillomatous lesions, vascular endothelial cells showed regenerative response, but the response was weak in large lesions. No such response was noted in invasive carcinomas; rather, cut-wounding induced collapse of blood vessels, which in turn induced massive coagulative necrosis of cancer cells. These responses can be interpreted to reflect exhausted vascular growth activity due to excessive stimulation by VEGF-overexpression, which was persistently seen from hyperplastic epidermis to invasive carcinoma.

Animals↗

PubMed1996

Genetic divergence in the clonal evolution of breast cancer.

The progression of ductal carcinoma in situ (DCIS) to infiltrating and metastatic cancer of the breast is thought to be a consequence of clonal expansions of neoplastic cells with progressively more genetic alterations. To study this progression, we first dissected multiple foci from each of 23 breast tumors with DCIS only and 20 cases with synchronous DCIS and infiltrating cancer. We than tested microsatellite markers by PCR for allelic losses in the individual foci for loci on chromosomes 6q, 9p, 11q, 13q, 16q, 17q, and 17p. The patterns of allelic losses identified in the in situ cancers were generally conserved in the synchronous infiltrating tumors, supporting the paradigm that the infiltrating tumors are clonally derived from the in situ lesions. However, in 8 (40%) of the 20 cases with synchronous in situ and invasive cancer, heterogeneous patterns of allelic loss at one or more chromosomal loci were observed in adjacent DCIS foci. Moreover, some of the allelic losses recognized in in situ portions of the tumors were not conserved in the clonal progression to the synchronous invasive tumor. Such allelic loss heterogeneity was noted in only 1 of the 20 infiltrating tumors and only 3 of the 23 cases of DCIS without invasion that were studied in a similar manner. This heterogeneity indicated genetic divergence during the clonal evolution of breast cancer, particularly at the time when in situ cancers progress to invasive cancers.

Breast Neoplasms↗

PubMed2004

Cytogenetic clonal evolution alone in CML relapse post-transplantation does not adversely affect response to imatinib mesylate treatment.

Good prognosis after imatinib mesylate treatment has been reported if cytogenetic clonal evolution (CE) is the only criterion of accelerated phase (AP) chronic myelogenous leukemia (CML). To evaluate the impact of CE upon imatinib treatment in post-transplant settings, responses and toxicities in the relapsed AP-CE were analyzed in comparison with those in the relapsed chronic phase (CP). Both CP (n=7) and AP-CE patients (n=6) received imatinib mesylate in an oral dose of 400 mg/day. Complete cytogenetic responses were obtained in six patients of each group, CP (86%) and AC-CE (100%), while molecular remission was seen in 43 and 50%, respectively. Granulocytopenia or thrombocytopenia of grade III or more occurred in four (57%) and two (33%) patients with CP and AP-CE, respectively. Nonhematological adverse events were mild and tolerable in both groups and only one (7%) of the 13 patients experienced recurrent graft-versus-host disease after imatinib treatment. Although this is a relatively small group of patients, we suggest that imatinib mesylate should be considered as a front-line treatment for relapsed CML as it showed the high response rate and low toxicity. We also suggest that CE alone is not an important factor in the induction of cytogenetic and molecular remissions in post-transplant relapse.

Adult↗

PubMed2006

Clonal evolution of lymphoblastoid cell lines.

Lymphoblastoid cell lines represent Epstein-Barr virus (EBV)-immortalized B lymphocytes, which are typically prepared by in vitro culture of normal blood cells. In this study, we evaluated the kinetics of clonal evolution in lymphoblastoid cell lines (LCLs) established from five different donors. Immunoglobulin heavy chain (IGH) and T-cell receptor gamma (TRG) gene rearrangements were tracked over time using PCR, while EBV clonality was tracked using Southern blot analysis of the viral terminal repeat fragment. All five cultures evolved towards monoclonal B cells within 8 weeks, while T lymphocytes disappeared over the same period. No significant association was found between the rapidity of clonal emergence and either the proliferation rate or the size of the EBV terminal repeat fragment, suggesting the random nature of clonal selection. Our results suggest that EBV-driven B lymphocytes rapidly progress from polyclonal to virtually monoclonal, which has implications for the pace at which lymphoma might evolve in vivo. In addition, our findings indicate that established lymphobastoid cell lines are not an ideal 'normal control' for human B lymphocytes because they do not represent the spectrum of polyclonal B cells found in healthy humans; instead, they primarily represent the progeny of a single B lymphocyte.

B-Lymphocytes↗

PubMedDate not supplied

Biological comparison between three clones of Trypanosoma cruzi and the strain of origin (Bolivia) with reference to clonal evolution studies.

After isolating three clones of Trypanosoma cruzi (Bolivia), we first characterized them according to parasitaemia, pleomorphism and virulence, and then histopathologically. The study's interest lies on the hypothesis that clonal evolution of T. cruzi has a major impact on biologically relevant properties of this parasite. Data obtained from the studies of parasitaemia, pleomorphism and virulence showed no differences between the groups studied. As a final point, the histopathological study shows us a muscular tissue tropism both in clones and in their mother strain (Bolivia). In this paper, we conclude that Bolivia strain and clones isolated from it, pertaining to the same major clone share similar biological properties.

Animals↗

PubMed1998

Progression of spontaneous lymphomas in SJL mice: monitoring in vivo clonal evolution with molecular markers in sequential splenic samples.

SJL mice are an inbred strain with a high incidence of spontaneous lymphomas of the B-cell type. We used molecular markers of clonality to study the process of tumor progression of SJL lymphomas in vivo. This was accomplished at time intervals ranging from 2 to 116 days by initial partial splenectomy (biopsy) followed by spleen sampling at the time of killing (autopsy). Immunoglobulin heavy chain (IgH) gene rearrangement and murine leukemia virus (MuLV) proviral integration patterns were used to study the clonal identities of the sequential tumor pairs in 11 informative mice by Southern blot hybridization. Of these 11 mice, 5 showed the same number of IgH gene rearrangement bands in the matched biopsy-autopsy samples, indicating the persistence of the original lesions. In 2 of 11 mice, a decrease in the number of IgH gene rearrangement bands was seen, consistent with a process of clonal selection in the original oligoclonal population. Another 2 of 11 mice showed an increase in the IgH gene rearrangement bands, indicating the emergence of either a new unrelated clone or, less likely, a subclone with secondary IgH gene rearrangement. The remaining two mice showed differences between the patterns in biopsy and autopsy samples, as assessed by IgH gene rearrangement and the proviral integration analysis. This finding suggests that the biopsied tumor had regressed and new clones had emerged. Tumor development was also associated with an increase in the number of clonal MuLV insertions in all mice except one, in which no non-germline integration band was detected. Of 11 mice, 5 showed an increase in the extent of tumor involvement by microscopic examination of the biopsy and autopsy samples; 3 showed a decrease, whereas 2 showed no change. A change in tumor morphology toward a more dedifferentiated appearance was found in only 1 of 11 mice. Overall, the results did not show a single paradigm that tumor progression followed, rather they indicated a complex and dynamic process of clonal evolution, which is likely to be a major feature of lymphoma progression in vivo.

Animals↗