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PubMed2004

Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases.

Among 2333 consecutive patients with myelofibrosis with myeloid metaplasia (MMM) seen at our institution, 91 fulfilled the World Health Organization (WHO) criteria for leukemic transformation (LT). All episodes of LT were myeloid in origin (acute myeloid leukemia [AML]) with all French-American-British (FAB) subtypes represented except M3; the most frequent subtypes were M7 (25.4%), M0 (22.4%), and M2 (17.9%). Cytogenetic studies during LT were available in 56 patients and revealed a clonal abnormality in 51 (91%): 30 patients had complex karyotype, 2 had core-binding factor gene lesions, and 18 had abnormalities of chromosome 5 or 7. Karyotypic evolution was documented in the majority of the patients in whom serial analysis was possible. In general, LT was fatal in 98% of the cases after a median of 2.6 months (range, 0-24.2 months). Twenty-four patients received AML-like induction chemotherapy that resulted in no complete remission: 41% reverted into chronic-phase disease and the incidence of treatment-related mortality was 33%. The remaining 67 patients received either supportive care alone (48 patients) or low-intensity chemotherapy (19 patients). Overall, survival was similarly poor in all 3 treatment categories. The outcome of LT in MMM with current therapies is dismal and either supportive care alone or appropriate clinical trials should be considered.

Adult↗
PubMed1990

The ecology and evolution of inducible defenses.

Inducible defenses are responses activated through a previous encounter with a consumer or competitor that confer some degree of resistance to subsequent attacks. While the importance of inducible resistance has long been known in host-parasite interactions, it is only recently that its importance has emerged in other natural systems. Although the structural defenses produced by invertebrates to their competitors and predators are by no means the same as an immune response triggered by parasites, these responses all share the properties of (1) specificity, (2) amplification and (3) memory. This review discusses the following ecological consequences and evolutionary causes of inducible defenses: (1) Inducible defenses render historical factors important in biological interactions and can affect the probability of individual survival and growth, as well as affect population dynamics of consumers in some circumstances. (2) Although the benefits of inducible defenses are often balanced by fitness costs, including reduced growth, reproductive output and survivorship, the role of costs and benefits in the evolution of inducible defenses is by no means clear. A more integrated approach would involve a multivariate analysis of the role of natural selection on the inducible characters of interest, their norms of reaction and correlated fitness characters. (3) The disproportionate representation of inducible, morphological defenses among clonal organisms may be due to both a higher rate of origination and enhanced selection to maintain these defenses in clonal taxa. (4) Inducible defenses should be most common when reliable cues are available, attacks by biological agents are unpredictable, and the fitness gains of defenses are balanced by the costs. An integrated approach to studying inducible defenses would thus combine mechanistic estimates of costs, population-level estimates of defense effectiveness, and genetic estimates of correlations between fitness and inducible characters. This will allow us to estimate rates of evolution in these phenotypically plastic threshold characters.

Animals↗
PubMed1997

Mathematical models of parasite responses to host immune defences.

We examine the evolution of microparasites in response to the immune system of vertebrate hosts. We first describe a simple model for an acute infection. This model suggests that the within-host dynamics of the microparasite will be a 'race' between parasite multiplication and a clonally expanding response by the host immune system, resulting either in immune-mediated clearance or host death. In this very simple model, in which there is only a single parasite and host genotype, maximum transmission is obtained by parasites with intermediate rates of growth (and virulence). We examine how these predictions depend on key assumptions about the parasite and the host, and consider how this model may be expanded to incorporate the effect of additional complexities such as host-parasite co-evolution, host polymorphism, and multiple infections.

Animals↗
PubMed2002

The clonal theory of parasitic protozoa: 12 years on.

The question of population structure in parasitic protozoa has recently gained a renewed topicality with significant contributions on medically important pathogens, such as Plasmodium falciparum, Toxoplasma gondii and Cryptosporidium parvum. The proposals that initiated this debate are reviewed here and the subsequent developments of the clonal theory, in light of recent contributions, are examined.

Animals↗
PubMed1996

Widespread clonal B-cell disorder in Sjögren's syndrome predisposing to Helicobacter pylori-related gastric lymphoma.

Helicobacter pylori has been identified as a critical antigenic stimulus to the development of gastric lymphoma, but additional factors should be required for such evolution. This topic is now of major importance to clarify the pathobiology of gastric lymphomagenesis. Peculiar autoimmune diseases, such as Sjögren's syndrome, are well known to predispose to B-cell lymphomas. We report on a patient with Sjögren's syndrome and a widespread B-cell lymphoproliferative disorder. A pathological picture of low-grade lymphoma was observed in the stomach, concomitantly with H. pylori infection. However, the B-cell disorder was definitely nonmalignant in the other tissues involved, i.e., the parotid gland and lymph nodes, which are the characteristic targets of Sjögren's syndrome-associated lymphoproliferation. After H. pylori eradication, a dramatic regression of gastric lymphoma into chronic gastritis was observed, but no amelioration occurred in the parotid and nodal involvement. Multiple molecular analyses showed the expansion of the same B-cell clone in synchronous and metachronous lymph node, parotid, and gastric lesions before and after H. pylori eradication. Thus, H. pylori played a crucial role in the local boosting of B-cell lymphoproliferation, but the underlying B-cell disorder was that associated with the autoimmune disease and was nonmalignant. The comprehensive clinical, pathological, and molecular approach allowed us to then distinguish the role of peculiar individual predisposing factors and of local infection in the pathobiology of mucosa-associated lymphoid tissue-associated lymphoproliferation.

Aged↗
PubMed2003

Extensive and divergent chromosomal losses in squamous and spindle-cell components of esophageal sarcomatoid carcinoma.

Sarcomatoid carcinoma of the esophagus is an unusual type of squamous cell carcinoma (SCC) with a variable component of sarcomatoid spindle cells (SA). The loss of heterozygosity (LOH) involving multiple cancer-associated chromosomal arms has been reported to have a concerted, rather than an individual, effect on tumor progression. In order to delineate the role of LOH in the evolution of a biphasic tumor, the carcinoma in situ (CIS), invasive squamous cell carcinoma (ISCC), and SA components from a sarcomatoid carcinoma of the esophagus were compared for their clonality and extent of LOH. Forty microsatellite markers on the cancer-associated chromosomes, 3p, 4p, 5q, 8p, 9p, 13q, 17p, and 18q, were used for the polymerase chain reaction-based LOH analysis. All eight sarcomatoid carcinomas tested revealed extensive LOHs, involving an average of seven chromosomal arms. All CIS, ISCC, and SA components carried not only a high-level primary LOH (mean chromosomal involvement, 5.3) in common but also a low-level secondary LOH (mean chromosomal involvement, 1.8) in disparity. Interestingly, more secondary LOHs were always burdened in the CIS (four cases) rather than the matched ISCC. SA had a greater (four cases), equal (one case), or fewer (one case) number of secondary LOHs than ISCC. Given that excessive chromosomal losses may confer a disadvantage for tumor growth or a benefit for a metaplastic transformation, these results suggest that the multidirectional differentiation of a SCC precursor is stimulated by extensive and divergent LOHs acquired at the initial or early stages, and a precursor burdened with excessive LOH either remains in CIS or expands as a SA component.

Aged↗
PubMed2006

Diversity of trematode genetic clones within amphipods and the timing of same-clone infections.

The genetic diversity of trematodes within second intermediate hosts has important implications for the evolution of trematode populations as these hosts are utilized after the parasites reproduce asexually within first intermediate hosts and before sexual reproduction within definitive hosts. We characterised the genetic clonal diversity of the marine trematode Maritrema novaezealandensis within amphipod (Paracalliope novizealandiae) second intermediate hosts using four to six microsatellite loci to determine if multiple copies of identical trematode clones existed within naturally infected amphipods. To determine the relative timing of infections by identical clones within hosts, trematode metacercariae were assigned to six developmental stages and the stages of identical clones were compared. The genotypes of 306 trematodes were determined from 44 amphipods each containing more than one trematode. Six pairs of identical trematode clones were recovered in total (representing five amphipods: 11% of amphipods with greater than one trematode) and all pairs of clones belonged to the same developmental stage. This suggests that identical clone infections are effectively synchronous. A general decrease in the number of metacercariae recovered, prevalence, and mean intensity of infection for each subsequent developmental stage coupled with large numbers of metacercariae (>9) only being recovered from recent infections, supports the occurrence of post-infection amphipod mortality and/or within-host trematode mortality. Taken together, our results indicate that natural infections are characterised by high genetic diversity, but that amphipods also periodically encounter "batches" of genetically identical clones, potentially setting the stage for interactions within and between clonal groups inside the host.

Amphipoda↗
PubMed2001

Allelic Variation within Helicobacter pylori babA and babB.

Helicobacter pylori strains show both geographic and disease-associated allelic variation. We investigated the diversity present in two genes, babA and babB, which are members of a paralogous family of outer membrane proteins. Eleven family members within a single H. pylori strain, predicted to encode proteins with substantial N- and C-terminal similarity to each other, were classified as babA paralogues. In their central regions, most are less than 54% related to one another. Examining the babA and babB central regions in 42 H. pylori strains from different geographic locales, we identified five different allele groups of babA (AD1 to AD5) and three different allele groups of babB (BD1 to BD3). Phylogenetic analysis revealed that the allelic groupings of babA and babB are independent of one another and that, for both, geographic variation is present. Analysis of synonymous and nonsynonymous substitutions in these regions showed that babA is more diverse, implying an earlier origin than that of the same region of babB, but that the babA diversity region may have more functional constraints. Although recombination has been central to the evolution of both genes, with babA and babB showing low mean compatibility scores and homoplasy ratios of 0.71 and 0.67, respectively, recombination is not sufficient to obscure evidence of clonal descent. Despite the involvement of babA in binding to the host blood group antigen Lewis B, neither the presence of different babA allele groups nor that of different babB allele groups is a determining factor in Lewis B binding of H. pylori strains.

Adhesins, Bacterial↗
PubMed2026

Genomic Evolution of Myeloproliferative Neoplasms and Therapy-Associated Mutagenesis.

UNLABELLED: Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts, but disease can progress to myelofibrosis or acute myeloid leukemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of hematopoietic colonies revealed age-appropriate polyclonal hematopoiesis in triple-negative essential thrombocythemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C > G mutations following azacitidine and characteristic T > A/T > G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate that progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis. SIGNIFICANCE: Longitudinal whole-genome sequencing shows MPN progression is genomically encoded years before clinical transformation, with distinct evolutionary routes to leukemia and MF. It identifies DNA mutagenesis associated with HC and 5-azacitidine, suggests some triple-negative cases are nonclonal, and supports serial clinical genomic monitoring for improved risk stratification and long-term management. See related commentary by Agarwal and Sankaran, p. 1724.

Humans↗
PubMed2005

Pediatric meningosarcoma: clinical evolution and genetic instability.

This report presents a female diagnosed with a frontoparietal interhemispheric meningosarcoma who, parallel to the clinical worsening, revealed an increase in the genetic instability (in bleomycin cultures) and the complexity of the karyotypes, with the acquisition of a clonal deletion of 17p13 (the locus for the TP53 tumor suppressor gene). The genetic findings of this patient suggest that the increased genetic instability could contribute to tumor progression as well as to treatment resistance, possibly in the background of the clonal deletion of TP53.

Child↗
PubMed1996

Variation and evolution of class I Mhc in sexual and parthenogenetic geckos.

We present the first Mhc class I sequences in geckos. We compared Mhc variation in gekkonid species that reproduce sexually (Hemidactylus frenatus, Lepidodactylus aureolineatus, L. moestus, L. sp. Arno, L. sp. Takapoto) to others reproducing parthenogenetically (H. garnotii, L. lugubris). These comparisons include the known maternal (L. moestus) and paternal (L. sp. Arno) ancestors of the asexual L. lugubris. Sequences similar to other vertebrate species were obtained from both nuclear and cDNA templates indicating that these sequences are derived from expressed class I Mhc loci. Southern blot analysis using gecko class I probes, revealed that parthenogenetic clonal lineages of independent evolutionary origin have no within-clone band variation at class I loci and that no detectable recombination between restriction sites had taken place. Variability in the sexual species was similar to mammalian taxa, i.e. class I genes are highly variable in outbreeding sexual populations. Sequence analysis of the alpha-2 domain of class I genes identified point mutations in a clonal lineage of L. lugubris which led to amino acid substitutions. Potential transspecific allelic lineages were also observed. The persistence of asexual lineages with little or no class I diversification over thousands of generations seems to argue against strong selection for Mhc multi-allelism caused by pathogen-Mhc allele specificity. On the other hand, the high level of heterozygosity in the parthenogenetic species (a consequence of their hybrid origin) may provide clonal lineages with adequate antigen presenting diversity to survive and compete with sexual relatives.

Amino Acid Sequence↗
PubMed2001

Demonstration of reinfection and reactivation in HIV-negative autopsied cases of secondary tuberculosis: multilesional genotyping of Mycobacterium tuberculosis utilizing IS 6110 and other repetitive element-based DNA fingerprinting.

SETTING: Secondary tuberculosis may follow reinfection or endogenous reactivation. The design of effective preventive and treatment protocols requires knowledge about the relative importance of these mechanisms in specific communities. Molecular typing of Mycobacterium tuberculosis has permitted linkage of cases and demonstration of patterns of inter- or intrapatient strain diversity correlating with reinfection and reactivation. OBJECTIVE: The use of DNA fingerprinting to examine intrapatient strain diversity in autopsied, HIV-negative individuals resident in a high incidence community. DESIGN: Autopsy (12 cases) and pneumonectomy (one case) permitted multilesional sampling for bacterial culture and comparative genotyping. Mycobacterium tuberculosis strains were typed using probes directed against IS 6110, the direct repeat sequence (DR) and MTB484(1). RESULTS: In two patients, the demonstration of pulmonary infection by two distinct strains suggested dual infection of these individuals. In one other case, the strain isolated from a Ghon-focus was identical to that obtained from all secondary cavitating lesions, which suggested reactivation of the primary infection. In the remaining cases, all isolates were identical, but primary lesions could not be identified with certainty or were culture negative. One of these cases showed evidence of strain evolution. CONCLUSIONS: Multilesional strain genotyping suggested both reinfection and reactivation in a series of HIV-negative autopsied patients with secondary tuberculosis. In most (11/13) cases, the same strain (or clonal variant) was present in all lesions, pulmonary and extrapulmonary.

AIDS-Related Opportunistic Infections↗
PubMed2003

Pre-natal, clonal origin of acute lymphoblastic leukaemia in triplets.

A unique case of ALL in three monozygotic triplets diagnosed at the age of 24, 27 and 37 months is described. Archived bone marrow smears were available for molecular analysis of immunoglobulin heavy chain (IGH) and IGK genes and T-cell receptor (TCR)-delta and gamma gene rearrangements. A shared IGH rearrangement was found in triplets "A" and "B", and an identical rearrangement of TCR-delta in triplets "B" and "C". These data suggest a common, monoclonal initiation of ALL in one of these three triplets, followed by dissemination of clonal progeny to the other twins via vascular anastomoses within the single, monochorionic placenta that they shared in utero. Differences in IGH rearrangements in diagnostic samples also indicates divergent subclonal evolution of the original "pre-leukaemic" clone.

Adult↗
PubMed2003

Atypical 16S rRNA gene copies in Ochrobactrum intermedium strains reveal a large genomic rearrangement by recombination between rrn copies.

Ochrobactrum intermedium is an opportunistic human pathogen belonging to the alpha 2 subgroup of proteobacteria. The 16S rDNA sequences of nine O. intermedium isolates from a collection of clinical and environmental isolates exhibited a 46-bp insertion at position 187, which was present in only one sequence among the 82 complete or partial 16S rDNA sequences of Ochrobactrum spp. available in data banks. Reverse transcription-PCR experiments showed that the 46-bp insertion remained in the 16S rRNA. The inserted sequence folded into a stem-loop structure, which took place in and prolonged helix H184 of the 16S rRNA molecule. Helix H184 has been described as conserved in length among eubacteria, suggesting the idiosyncratic character of the 46-bp insertion. Pulsed-field gel electrophoresis experiments showed that seven of the clinical isolates carrying the 46-bp insertion belonged to the same clone. Insertion and rrn copy numbers were determined by hybridization and I-CeuI digestion. In the set of clonal isolates, the loss of two insertion copies revealed the deletion of a large genomic fragment of 150 kb, which included one rrn copy; deletion occurred during the in vivo evolution of the clone. Determination of the rrn skeleton suggested that the large genomic rearrangement occurred during events involving homologous recombination between rrn copies. The loss of insertion copies suggested a phenomenon of concerted evolution among heterogeneous rrn copies.

Alphaproteobacteria↗
PubMed1996

Chronic B-cell lymphocytosis with binucleated lymphocytes (LWBL): a review of 38 cases.

LWBL is characterized by persistent and stable lymphocytosis, seen in but not exclusively female patients, with binucleated lymphocytes evident on peripheral blood smears. There is a polyclonal increase of serum IgM and in all cases immunophenotyping revealed a polyclonal expansion of B-lymphocytes. Whether this syndrome represents a premalignant disease process or a true polyclonal lymphocytosis remains unsettled. The occasional reports of clonal Ig rearrangements in this disorder suggest that in a minority of cases the polyclonal expansion may be followed by the emergence of one predominant clone. The demonstration of a clinically, benign, clonal lymphoid population is well recognised in several T cell disorders such as in the syndrome of large granular lymphocytes expansion. The benign clinical course and the lack of biological evolution in the majority of cases suggest that the importance of recognition of this disorder lies in avoiding aggressive therapy in these cases. A careful follow-up of these patients is mandatory and prospective immunological and genetic studies performed at different stages of the disease may well clarify this issue, particularly since most patients were HLA-DR7 positive.

Adult↗
PubMed2000

[A virus called HTLV-1. Epidemiological aspects].

GEOGRAPHIC DISTRIBUTION AND TRANSMISSION: HTLV-1 is not an ubiquitous virus. 15 to 25 million subjects are estimated to be infected. Endemic areas are recognized in southern Japan, tropical Africa, the Caribbean, some areas in Central and South America, and in few regions of the Middle East and Melanesia. In these endemic zones, 0.5 to 50% of the population, depending on age and gender, have specific antibodies against HTLV-1 antigens. Interhuman transmission can occur from mother to child by prolonged breast feeding, from men to women by sexual intercourse, and from blood exposure via infected lymphoid cells. MOLECULAR EPIDEMIOLOGY: Molecular epidemiology studies have evidenced several molecular types or genotypes of HTLV-1 linked to the geographical origin of the infected population rather than to the associated pathology (leukemia versus neuromyelopathy). The high stability of the HTLV-1 genome is probably related to clonal expansion of infected cells conjugated to the minimal use of the reverse transcriptase. This low variability has been used as a molecular tool to better understand the origin, the evolution and the dissemination of this retrovirus. The current distribution of HTLV-1, and its simian homologue STLV-1, results from at least 4 events: transmission of STLV-1 between different monkey species, transmission of STLV-1 to humans, persistence of HTLV-1 in isolated human populations, and finally global and more recent distribution of HTLV-1 (mainly the cosmopolite subtype) subsequent to migration of virus-infected populations.

Animals↗
PubMed2005

How old are the extant lineages of Toxoplasma gondii?

Most known isolates of Toxoplasma gondii belong to one of only three lineages, which are presumed to be clonal. Three models have been proposed for the evolutionary relationship of these lineages to the other extant lineages: Model (a) proposing that all lineages are derived from a most recent common ancestor (MRCA) in the distant past, Model (b) that all lineages are derived from a MRCA in the very recent past, and Model (c) that the clonal lineages share a recent MRCA but are related to the other lineages only in the distant past. Here, I test these models using DNA intron and coding-sequence data for loci at 14 genes, using three different methods to calculate the time of the MRCA. All of the calculations agree that the MRCA of the clonal lineages was > 70% of the age of the MRCA of all lineages, thus favouring Model (a). The MRCA may have existed approximately 150,000 years ago, with the clonal lineages expanding in prevalence approximately 10,000 years ago.

Animals↗
PubMed1994

Karyotype and prognosis in non-Hodgkin lymphoma.

In malignant non-Hodgkin lymphomas (NHL), cytogenetic analysis may provide prognostic information including prediction of histologic evolution and responsiveness to therapy. In this study, we correlate clinical data and chromosomal aberrations in 70 adult patients with newly diagnosed NHL followed for a median of 20 months. Clonal aberrations were detected in 68/70 patients (97%). Besides t(2;5)(p23;q35), observed exclusively in three patients with anaplastic large cell lymphoma, Ki-1 positive, none of the characteristic aberrations observed was specific for a given histological subtype. Aberrations of chromosome 7 (n = 21) occurred in all histological subtypes together with aberrations of chromosome 3 and of the short arm of chromosome 17. They were clinically associated with a high serum lactate dehydrogenase level (LDH) and a trend to short survival. Anomalies of the long arm of chromosome 13 (n = 10) were found in patients with high grade B-cell lymphomas and bulky disease. In t(14;18)(q32;q21) bearing lymphomas (n = 27), distinct patterns of additional aberrations were observed in low grade and high grade lymphomas: trisomy 3 and trisomy 18 occurred concomitantly in high grade lymphomas (n = 6, p < 0.001) as well as aberrations of 1q, 5q, 6q and +der (18)(q21). In conclusion, cytogenetic analysis provides information about the complexity of genetic changes in NHL. These changes act not only as indicators of disease activity, but influence clinical outcome as demonstrated by their stringent correlation to the International Index and might reveal more general rules of tumor growth and spreading.

Adolescent↗