[Partial sequence of fragment Fc' of mouse clonal immunoglobulin].
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Amino Acids↗
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Chromosome abnormalities and karyotypic evolution in 83 patients with myelodysplastic syndrome and predictive value for prognosis.
In a chromosome study of 83 patients with myelodysplastic syndrome (MDS), 50 showed a clonally abnormal karyotype. The most frequent abnormalities were the whole or a partial loss of the long arm of chromosome 7 (-7 or 7q-) (14 patients) and a partial loss of the long arm of chromosome 5 (5q-) (11 patients). Twenty patients with 5q- and/or -7 or 7q- had a shorter survival (median, 5 months) than those with other abnormal karyotypes (22 months) or those with a normal karyotype (28 months). In this series 30 patients were examined cytogenetically on two or more occasions during the course of their illness. Ten patients showed a further karyotypic alteration from the initial findings, and, concomitantly, their disease progressed in severity including overt leukemia. These patients had a shorter survival (median, 2 months) after the chromosome reanalysis than the other 20 patients who did not have further karyotypic changes (21 months). Thus, the prognosis of patients with MDS can be predicted more accurately by reanalyzing the chromosomes after the initial analysis.
Adult↗
Sexual reproduction and the evolution of microbial pathogens.
Three common systemic human fungal pathogens--Cryptococcus neoformans, Candida albicans and Aspergillus fumigatus--have retained all the machinery to engage in sexual reproduction, and yet their populations are often clonal with limited evidence for recombination. Striking parallels have emerged with four protozoan parasites that infect humans: Toxoplasma gondii, Trypanosoma brucei, Trypanosoma cruzi and Plasmodium falciparum. Limiting sexual reproduction appears to be a common virulence strategy, enabling generation of clonal populations well adapted to host and environmental niches, yet retaining the ability to engage in sexual or parasexual reproduction and respond to selective pressure. Continued investigation of the sexual nature of microbial pathogens should facilitate both laboratory investigation and an understanding of the complex interplay between pathogens, hosts, vectors, and their environments.
Animals↗
Cytogenetic heterogeneity of genetically marked and metastatically competent "dominant" tumor cell clones.
Examination of tumors usually shows them to consist of phenotypically and clonally heterogeneous cell subpopulations. On the other hand, previous studies from our laboratory have provided compelling evidence for the rapid evolution, or overgrowth, of single "dominant" clones during the course of primary tumor growth. Thus in one such study, syngeneic CBA mice were injected with a mixture of 50-100 different genetically tagged clones of a mouse mammary carcinoma called SP1. The vast majority of these clones were non-metastatic. The different clones were tagged by random integrations of foreign DNA using calcium phosphate-mediated transfection of the plasmid pSV2neo, the resultant primary tumors were found to consist of a single dominant clone, called B5, which was also shown to be metastatically competent. The detection of single dominant clones such as B5 in primary tumors can be reconciled with the concept of tumor cell heterogeneity if it could be shown that the dominant clone was in fact heterogeneous for other genetic or phenotypic markers, i.e., was homogeneous only for the plasmid-based genetic marker used for its detection. To study this question, we examined the karyotypes of several sublines of B5, two derived from a primary advanced tumor and one from a spontaneous lung metastasis. We indeed found evidence to support the existence of marked cellular heterogeneity within and between the three sublines examined. Thus, while all three retained common cytogenetic markers, each also expressed unique markers. Moreover, karyotypic heterogeneity within a given subline was observed. Thus the concept of clonal dominance of primary tumors by metastatically competent cell subpopulations is not incompatible with the concept of the cellular heterogeneity of tumors. The implications of the results are discussed.
Adenocarcinoma↗
Directed evolution of human T-cell receptors with picomolar affinities by phage display.
Peptides derived from almost all proteins, including disease-associated proteins, can be presented on the cell surface as peptide-human leukocyte antigen (pHLA) complexes. T cells specifically recognize pHLA with their clonally rearranged T-cell receptors (TCRs), whose natural affinities are limited to approximately 1-100 muM. Here we describe the display of ten different human TCRs on the surface of bacteriophage, stabilized by a nonnative interchain disulfide bond. We report the directed evolution of high-affinity TCRs specific for two different pHLAs: the human T-cell lymphotropic virus type 1 (HTLV-1) tax(11-19) peptide-HLA-A(*)0201 complex and the NY-ESO-1(157-165) tumor-associated peptide antigen-HLA-A(*)0201 complex, with affinities of up to 2.5 nM and 26 pM, respectively, and we demonstrate their high specificity and sensitivity for targeting of cell-surface pHLAs.
Antibody Affinity↗
Stepwise development of chromosomal abnormalities in angioimmunoblastic lymphadenopathy.
Cytogenetic studies of lymphoproliferative diseases, such as angioimmunoblastic lymphadenopathy (AILD), may provide a clue to the understanding of tumor development. Angioimmunoblastic lymphadenopathy may evolve from a nonmalignant lymphoproliferation into a peripheral T-cell lymphoma or even into a high-grade B-cell lymphoma and thus offers the chance to observe cytogenetic changes during lymphoma development. We report the cytogenetic findings in 24 cases of AILD. They are discussed together with 18 previously published cases from the same series. A striking feature was that unrelated chromosome abnormalities, both clonal and nonclonal, were frequently observed. Eighteen of 25 cases with aberrant clones show trisomy 3 (a characteristic chromosome abnormality in peripheral T-cell lymphoma), trisomy 5, or both. This finding provides cytogenetic evidence that these cases are definitely peripheral T-cell lymphomas. From the results of the 42 cases, hypotheses of stepwise evolution of the chromosome abnormalities in AILD are deduced: the first step is the appearance of chromosome abnormalities in different cells because of a genetic instability. At this time, clonal proliferation of T cells was already demonstrated by the rearrangement of T-cell receptor genes. As a second step, chromosomally aberrant clones become established. A cytogenetically detectable monoclonal proliferation represents the third step.
Aged↗
Genetic and phenotypic heterogeneity of human malignancies: finding order in chaos.
The presence of cellular heterogeneity within human tumors has been recognized for many years. Current concepts regarding the clonal origin of human neoplasms, and recent advances in the study of successive genetic changes that occur during tumor evolution may now make it possible to understand in greater depth the biological and clinical implications of intra-tumor heterogeneity at both the phenotypic and genotypic levels. In order to explore these concepts further, and to better identify the potential contributions that flow and image cytometry can make to our understanding of tumor heterogeneity, a session of the 1994 ISAC Congress was dedicated to plenary presentations on human cancer cell heterogeneity. Here, we provide a brief overview of the genetic evolutionary progression of human cancers, some considerations of clinically important phenotypic and genotypic markers, and an outline that might serve as a basis for framing relevant issues that are ammenable to further study. All Nature is but Art, unknown to thee; All Chance, Direction, which thou canst not see; All Discord, Harmony not understood: All partial Evil, universal Good. (Alexander Pope, Essay on Man, end of Epistle 1).
Biological Evolution↗
Cytogenetic findings in 179 patients with myelodysplastic syndromes.
Cytogenetic analyses were performed on 266 bone marrow and peripheral blood samples from 179 patients with myelodysplastic syndromes (MDS). According to the FAB classification, 42 patients presented with RA, 18 with RARS, 37 with RAEB, 22 with CMML, and 29 with RAEB-T. Nine patients showed a secondary MDS (S MDS). FAB classification was not available for 22 patients. Clonal karyotype anomalies were found in 92 patients (51.4%). Complex chromosome abnormalities occurred in 17 (18.5%) of them. An evolution of the karyotype was detected in 16 cases (17.4%). Cytogenetically independent cells or cell clones were found in eight patients. Nonclonal chromosome abnormalities were uncovered in 29 (16.2%) of the 179 MDS patients. Consecutive studies were performed in 48 patients and revealed a good correlation of initial karyotype and clinical course. The most frequent single anomalies were 5q- in 29 (31.5%), -7 in 22 (23.9%), trisomy 1q in 14 (15.2%), and +8 in 13 (14.1%) of 92 patients respectively. Our cytogenetic findings are presented in detail and discussed in relation to patients' age, morphological classification, clinical course, and prognostic impact. The contribution of cytogenetic findings to the delineation of multistep pathogenesis of MDS with special emphasis to karyotype instability is demonstrated.
Adult↗
Varicella-zoster viral meningitis mimicking lymphoma.
We report the case of a 30-year-old HIV-infected man admitted for a meningeal syndrome and a zoster rash. The CSF had cytological features suggesting a primary CNS lymphoma (PCNSL). The large lymphoid cells had a fine chromatin with nucleoli, a basophilic cytoplasm with azurophilic granules and high mitotic activity. Several arguments demonstrated the viral origin of the meningitis: the large lymphoid cells were of T origin with no evidence of clonal TCR gamma gene rearrangement. The PCR was positive for Varicella-Zoster Virus (VZV) and EBV DNA. Clinical evolution was favorable under acyclovir. We should be cautious in the differential diagnosis between viral meningitis and PCNSL.
Adult↗
Molecular intermediates of fitness gain of an RNA virus: characterization of a mutant spectrum by biological and molecular cloning.
The mutant spectrum of a virus quasispecies in the process of fitness gain of a debilitated foot-and-mouth disease virus (FMDV) clone has been analysed. The mutant spectrum was characterized by nucleotide sequencing of three virus genomic regions (internal ribosome entry site; region between the two AUG initiation codons; VP1-coding region) from 70 biological clones (virus from individual plaques formed on BHK-21 cell monolayers) and 70 molecular clones (RT--PCR products cloned in E. coli). The biological and molecular clones provided statistically indistinguishable definitions of the mutant spectrum with regard to the distribution of mutations among the three genomic regions analysed and with regard to the types of mutations, mutational hot-spots and mutation frequencies. Therefore, the molecular cloning procedure employed provides a simple protocol for the characterization of mutant spectra of viruses that do not grow in cell culture. The number of mutations found repeated among the clones analysed was higher than expected from the mean mutation frequencies. Some components of the mutant spectrum reflected genomes that were dominant in the prior evolutionary history of the virus (previous passages), confirming the presence of memory genomes in virus quasispecies. Other components of the mutant spectrum were genomes that became dominant at a later stage of evolution, suggesting a predictive value of mutant spectrum analysis with regard to the outcome of virus evolution. The results underline the observation that greater insight into evolutionary processes of viruses may be gained from detailed clonal analyses of the mutant swarms at the sequence level.
Adaptation, Physiological↗
Cell-selfish modes of evolution and mutations directed after transcriptional bypass.
During transcription, prokaryotic and eukaryotic RNA polymerases bypass and misread (transcriptional mutagenesis) several classes of DNA lesions. For example, misreading of 8-OH-dG generates mRNAs containing G to T transversions. After translation, if the mutant protein briefly allowed the cell a growth-DNA replication advantage, then precocious DNA replication would bypass that unrepaired 8-OH-dG and misinsert dA opposite the directing DNA lesion with a higher probability than would be experienced for 8-OH-G lesions at other positions in otherwise identical neighboring cells. Such retromutations would have been tested for their imparted growth advantage as mRNA before they became heritable DNA mutations. The logical properties of a mode of evolution that utilizes directed-retromutagenesis were compared one by one with those of the standard neo-Darwinian mode. The retromutagenesis mode, while minimizing mutational load, is cell-selfish; fitness is for an immediate growth advantage rather than future reproductive potential. In prokaryotes, an evolutionary mode that involves standard Darwinian fitness testing of novel alleles in the genetic background of origin followed by clonal expansion also favors cell-selfish allele combinations when linkage disequilibrium is practiced. For metazoa and plants to have evolved organized tissues, cell-selfish modes of evolution represent systems-poisons that must be totally suppressed. The feedback loops that allow evolution to be cell-serving in prokaryotes are actively blocked in eukaryotes by traits that restrict fitness to future reproductive potential. These traits include (i) delay of fitness testing until after the mutation is made permanently heritable, (ii) diploidy to further delay fitness testing, (iii) segregation of somatic lines from germ lines, (iv) testing of novel alleles against randomized allele combinations constructed by obligate sex, and (v) obligate genetic death to insure that that the most basic systems unit of selfish allele combinatorial uniqueness is the species instead of the cell. The analyses indicate that modes of evolution in addition to our neo-Darwinian one could have existed utilizing known molecular mechanisms. The evolution of multicellularity was as much the discarding of old cell-selfish habits as the acquisition of new altruistic ones.
Alleles↗
Evolution of the T cell receptor beta repertoire from synovial fluid T cells of patients with juvenile onset rheumatoid arthritis.
OBJECTIVE: To determine the level of T cell clonal expansion and the proportion of T cells that persist over time in the synovial fluid (SF) of patients with juvenile onset rheumatoid arthritis (JRA). METHODS: We collected SF samples from each of 3 patients with JRA at 2 to 3 year intervals. To measure expression across the entire spectrum of Vbeta families in each of 7 fluids examined, we synthesized and amplified dscDNA from all 24 Vbeta families with a single reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: The proportion of clonally expanded T cells and persistent T cells is low and variable among patients. CONCLUSION: The data are supportive of disease models not centered on T cells but centered on the changing nature of the disease over time.
Age of Onset↗
A phylogenetic method for detecting positive epistasis in gene sequences and its application to RNA virus evolution.
RNA virus genomes are compact, often containing multiple overlapping reading frames and functional secondary structure. Consequently, it is thought that evolutionary interactions between nucleotide sites are commonplace in the genomes of these infectious agents. However, the role of epistasis in natural populations of RNA viruses remains unclear. To investigate the pervasiveness of epistasis in RNA viruses, we used a parsimony-based computational method to identify pairs of co-occurring mutations along phylogenies of 177 RNA virus genes. This analysis revealed widespread evidence for positive epistatic interactions at both synonymous and nonsynonymous nucleotide sites and in both clonal and recombining viruses, with the majority of these interactions spanning very short sequence regions. These findings have important implications for understanding the key aspects of RNA virus evolution, including the dynamics of adaptation. Additionally, many comparative analyses that utilize the phylogenetic relationships among gene sequences assume that mutations represent independent, uncorrelated events. Our results show that this assumption may often be invalid.
DNA Mutational Analysis↗
Pre-malignant and malignant lymphoproliferations in an HCV-infected type II mixed cryoglobulinemic patient are sequential phases of an antigen-driven pathological process.
Type II mixed cryoglobulinemia (MC) is a systemic vasculitis characterized by the presence in the serum of a monoclonal cryoprecipitable IgM with rheumatoid factor (RF) activity. Hepatitis C virus (HCV) has been recognized as its major etiologic factor. Because MC frequently evolves into overt B-cell non-Hodgkin's lymphoma (NHL), chronic HCV infection is hypothesized to lead to both benign and malignant lymphoproliferative disease. In this study, we investigated mutations in the V(H) and V(K) genes of the B-cell clone originating the overt B-cell lymphoma in a subject with MC. Mutational patterns were analyzed longitudinally in two bone marrow biopsies obtained at the stage of MC, as well as in multiple involved tissues (bone marrow, liver, and peripheral blood cells) at the stage of overt NHL. Hybridization of variable-diversity-joining (VDJ) PCR products with a probe specific for the neoplastic clone indicated that the lymphoma originated from one of the clones over-stimulated during MC. This clone producing an IgM highly homologous to a protein with RF specificity may explain the MC syndrome in the patient. Moreover, the presence of an IgH ongoing mutation process and the expression of an Ig antigen receptor significantly homologous to an anti-HCV protein support the hypothesis that the MC syndrome and the subsequent evolution to NHL are antigen-driven lymphoproliferative processes possibly sustained by HCV. Furthermore, the marked reduction in intra-clonal diversity in the last bone marrow biopsy obtained at the stage of overt NHL points out a minor dependence of the cells on the antigen-driven mechanism, although an intrinsic propensity of the neoplastic cell to undergo replacement mutations cannot be excluded.
Amino Acid Sequence↗
Genetic exchange and plasmid transfers in Borrelia burgdorferi sensu stricto revealed by three-way genome comparisons and multilocus sequence typing.
Comparative genomics of closely related bacterial isolates is a powerful method for uncovering virulence and other important genome elements. We determined draft sequences (8-fold coverage) of the genomes of strains JD1 and N40 of Borrelia burgdorferi sensu stricto, the causative agent of Lyme disease, and we compared the predicted genes from the two genomes with those from the previously sequenced B31 genome. The three genomes are closely related and are evolutionarily approximately equidistant ( approximately 0.5% pairwise nucleotide differences on the main chromosome). We used a Poisson model of nucleotide substitution to screen for genes with elevated levels of nucleotide polymorphisms. The three-way genome comparison allowed distinction between polymorphisms introduced by mutations and those introduced by recombination using the method of phylogenetic partitioning. Tests for recombination suggested that patches of high-density nucleotide polymorphisms on the chromosome and plasmids arise by DNA exchange. The role of recombination as the main mechanism driving B. burgdorferi diversification was confirmed by multilocus sequence typing of 18 clinical isolates at 18 polymorphic loci. A strong linkage between the multilocus sequence genotypes and the major alleles of outer-surface protein C (ospC) suggested that balancing selection at ospC is a dominant force maintaining B. burgdorferi diversity in local populations. We conclude that B. burgdorferi undergoes genome-wide genetic exchange, including plasmid transfers, and previous reports of its clonality are artifacts from the use of geographically and ecological isolated samples. Frequent recombination implies a potential for rapid adaptive evolution and a possible polygenic basis of B. burgdorferi pathogenicity.
Amino Acid Sequence↗
Genomic diversity of Erwinia carotovora subsp. carotovora and its correlation with virulence.
We used genetic and biochemical methods to examine the genomic diversity of the enterobacterial plant pathogen Erwinia carotovora subsp. carotovora. The results obtained with each method showed that E. carotovora subsp. carotovora strains isolated from one ecological niche, potato plants, are surprisingly diverse compared to related pathogens. A comparison of 23 partial mdh sequences revealed a maximum pairwise difference of 10.49% and an average pairwise difference of 2.13%, values which are much greater than the maximum variation (1.81%) and average variation (0.75%) previously reported for Escherichia coli. Pulsed-field gel electrophoresis analysis of I-CeuI-digested genomic DNA revealed seven rrn operons in all E. carotovora subsp. carotovora strains examined except strain WPP17, which had only six copies. We identified 26 I-CeuI restriction fragment length polymorphism patterns and observed significant polymorphism in fragment sizes ranging from 100 to 450 kb for all strains. We detected large plasmids in two strains, including the model strain E. carotovora subsp. carotovora 71. The two least virulent strains had an unusual chromosomal structure, suggesting that a particular pulsotype is correlated with virulence. To compare chromosomal organization of multiple enterobacterial genomes, several genes were mapped onto I-CeuI fragments. We identified portions of the genome that appear to be conserved across enterobacteria and portions that have undergone genome rearrangements. We found that the least virulent strain, WPP17, failed to oxidize cellobiose and was missing several hrp and hrc genes. The unexpected variability among isolates obtained from clonal hosts in one region and in one season suggests that factors other than the host plant, potato, drive the evolution of this common environmental bacterium and key plant pathogen.
Aconitate Hydratase↗
Molecular analysis of immunoglobulin genes in multiple myeloma.
The study of immunoglobulin genes in multiple myeloma over the last five years has provided important information regarding biology, ontogenetic location, disease evolution, pathogenic consequences and tumor-specific therapeutic intervention with idiotypic vaccination. Detailed analysis of V(H) genes has revealed clonal relationship between switch variants expressed by the bone marrow plasma cell and myeloma progenitors in the marrow and peripheral blood. V(H) gene usage is biased against V4-34 (encoding antibodies with cold agglutinin specificity; anti-l/i) explaining the absence of autoimmune phenomena in myeloma compared to other B-cell lymphoproliferative disorders. V(H) genes accumulate somatic hypermutations following a distribution compatible with antigen selection, but with no intraclonal heterogeneity. V(L) genes indicate a bias in usage of VkappaI family members and somatic hypermutation, in line with antigen selection, of the expressed Vkappa genes is higher than any other B-cell lymphoid disorder. A complementary imprint of antigen selection as evidenced by somatic hypermutation of either the V(H) or V(L) clonogenic genes has been observed. The absence of ongoing somatic mutations in either V(H) or V(L) genes gives rise to the notion that the cell of origin in myeloma is a post-germinal center memory B-cell. Clinical application of sensitive PCR methods in order to detect clonal immunoglobulin gene rearrangements has made relevant the monitoring and follow-up of minimal residual disease in stem cell autografts and after myeloablative therapy. The fact that surface immunoglobulin V(H) and V(L) sequences constitute unique tumor-specific antigenic determinants has stimulated investigators to devise strategies aiming to generate active specific immunity against the idiotype of malignant B-cells in myeloma by constructing vaccines based on expressed single-chain Fv fragments, DNA plasmids carrying V(H)+V(L) clonogenic genes for naked DNA vaccination, or dendritic cell-based vaccination armed with the tumor-specific idiotype.
B-Lymphocytes↗
The rate of homozygous CDKN2A/p16 deletions in glioma cell lines and in primary tumors.
The rate of homozygous deletions of CDKN2A/p16 is variable between different tumor entities, and in addition it is higher in established cell lines in comparison with primary tumors. Such incongruencies may reflect statistical sampling errors, true differences depending on tissue derivatisation and CDKN2A/p16 loss under selective pressure in tissue culture. Clarification of these issues is warranted in the context of defining tumor suppressor genes such as CDKN2A/p16 as targets for gene replacement therapies. We therefore compared established cell lines derived from human glioblastomas and their corresponding primary tumors by multiplex PCR methodology. Archival early passages were included to determine the time point at which the p16 status of a cell line changes if it is different from the original tumor. It was found that in 2 of 11 cases (18%) the primary tumor had no p16 alteration whereas the corresponding cell lines had a homozygous p16 deletion. Tracking the in vitro evolution of these two cell lines we found that CDKN2A/p16 was lost already in the earliest passages. This suggests a clonal outgrowth advantage of a subpopulation of p16 deleted tumor cells rather than instability of the CDKN2A/p16 genotype in vitro. Including 20 additional glioblastoma-derived cell lines we detected that in 19 of the total 31 lines at least one exon was lost bringing the rate of p16 loss in the whole panel to 61%. This compares to a rate of 49% which was found in original glioma tissue from 47 unselected other patients. It is concluded, that in cell culture selective pressure favours the outgrowth of pre-existing CDKN2A/p16 negative clones, which account for the difference of CDKN2A/p16 status between cell lines and tumors. In no case did we see a change of the CDKN2A/p16 status during prolonged tissue culture periods of up to 8 years.
Adult↗