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PubMed1981

Coexistence of myeloid and lymphoid neoplastic subpopulations in chronic myelogenous leukemia.

Serial cytogenetic studies have been performed on a child with Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML) and correlated with clinical, morphologic, and cytochemical data in an attempt to elucidate further the natural history of leukemia progression observed in this disease. Once the initial blast crisis had occurred, two genetically different leukemic clones of cells, one presumably having arisen from the other, coexisted throughout the remainder of the patient's course. The initial clone comprised differentiating myeloid cells, while the second clone appeared on morphologic and cytochemical grounds to be lymphoid and blastic. A dynamic equilibrium existed between these two populations of cells, with the balance altered by chemotherapy and/or other selective pressures. The leukemic progression demonstrated in this case is consistent with the concept of clonal evolution of malignant cell populations. In planning therapy, it may be necessary to consider each of these coexistent clones and their different therapeutic requirements.

Child, Preschool↗

PubMed2004

Genetic lineage of poorly differentiated gastric carcinoma with a tubular component analysed by comparative genomic hybridization.

Analysis of cell lineage is based on the use of genetic markers inherent to the lineage to be analysed. The breakpoints of unbalanced translocations, and the pattern of chromosomal loss/gain determined by comparative genomic hybridization (CGH), have been previously used to demonstrate lineages in diffuse-type gastric carcinoma. Signet ring cell carcinoma was shown to progress to poorly differentiated adenocarcinoma, and early diffuse-type gastric carcinoma to advanced diffuse-type gastric carcinoma. The present study focuses on poorly differentiated adenocarcinoma with a tubular component to clarify its derivation. CGH and array CGH were applied to DNA extracted from multiple portions of individual tumours and amplified by degenerate oligonucleotide-primed (DOP) PCR and the changes common to the samples in each tumour (stemline changes) were compared between the tumours with and those without a tubular component. Within individual tumours, the samples from the tubular component and those from the other components had common stemline changes and a very similar frequency pattern of chromosomal changes, indicating their common derivation. Frequent stemline changes were 8q+, 7p+, 3q+, 20q+, and 10p+, and these were different from those in the tumours without a tubular component. It was noticed that there were two subgroups in the tumours with a tubular component: one with 5p+, 6p+, 7p+, and 10p+, and the other without these changes. The latter had cytogenetic and clinicopathological features similar to those of the tumours without a tubular component. Analysis of the clonal evolution process by constructing dendrograms for each tumour gave results consistent with the notion that the latter subgroup may derive from signet ring cell carcinoma and the former from tubular adenocarcinoma.

Adenocarcinoma↗

PubMed2005

Diagnosis and treatment of children with aplastic anemia.

BACKGROUND: Long-term survival rates among children diagnosed with severe aplastic anemia (SAA) are excellent due to the success of human leukocyte antigen (HLA)-identical related hematopoietic stem cell transplantation (HSCT), concurrent advances in immunosuppressive treatment (IST), and improved supportive care. The challenge in making treatment recommendations for children with SAA, therefore, is to balance the apparent chronicity and morbidity following IST, with the potential up-front toxicity and complications of HSCT. METHODS: This review provides an update on the diagnosis and a risk-based treatment algorithm for children with acquired SAA. Recent experience using alternative donor HSCT and efforts to extend HSCT eligibility through advances in donor matching, de-escalation of conditioning regimens, and potential marrow graft engineering are highlighted. We discuss IST response rates, risks of relapse, and complications including clonal evolution. CONCLUSIONS: While good treatment options exist for a majority of children diagnosed with SAA, novel non-transplantation treatments for unresponsive and relapsed patients without suitable transplant donors are needed. Further improvements in outcome will ultimately require a more complete understanding of the pathophysiology of aplastic anemia (AA).

Anemia, Aplastic↗

PubMed1987

Biology of myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) represent a diverse spectrum of disorders ranging from refractory anemia to a preleukemic state. Peripheral cytopenias, cellular marrow, dysplasias and dysfunctions of myeloid and lymphoid cells constitute hematological hallmarks, and are caused by ineffective hemopoiesis. Investigations of cell cultures and cellular functions indicate that the disease originates in a stem cell pluripotent to all myeloid cells and possibly lymphoid cells as well. The disease commonly runs a chronic indolent course, often terminating in acute leukemia or nonleukemic death, notably infections and/or hemorrhage due to cytopenias and cellular dysfunctions. Clonal expansion or clonal evolution appears to be related to the disease progression with a greater degree of malignancy. However, the initial sequence of events causing damage to stem cells is still undefined.

Hematopoietic Stem Cells↗

PubMed1992

Absence of point mutation of N-ras oncogene in bone marrow cells with aplastic anemia.

Point mutation of N-ras oncogene at codons 12, 13 and 61 was studied in the bone marrow cells of patients with typical aplastic anemia using the polymerase chain reaction method for DNA amplification and dot blot hybridization to synthetic oligonucleotide probes. Point mutation was observed in none of the 15 patients studied. These findings indicate either that the pathogenesis of typical aplastic anemia is different from that of preleukemic states of myelodysplastic syndrome or acute leukemia in clonal evolution, or that the overlapping area sharing a common pathogenesis is much smaller than was presumed.

Anemia, Aplastic↗

PubMed1998

Telomere length dynamics in telomerase-positive immortal human cell populations.

It has been proposed that the progressive shortening of telomeres in somatic cells eventually results in senescence. Previous experiments have demonstrated that many immortal cell lines have acquired telomerase activity leading to stabilization of telomere length. Telomere dynamics and telomerase activity were examined in the telomerase-positive immortal cell lines HeLa and 293 and subclones derived from them. A mass culture of HeLa cells had a stable mean telomere length over 60 population doublings (PD) in vitro. Subclones of this culture, however, had a range of mean telomere lengths indicating that telomeric heterogeneity exists within a population with a stable mean telomere length. Some of the subclones lacked detectable telomerase activity soon after isolation but regained it by PD 18, suggesting that at least some of the variation in telomere length can be attributed to variations in telomerase activity levels. 293 subclones also varied in telomere length and telomerase activity. Some telomerase-positive 293 subclones contained long telomeres that gradually shortened, demonstrating that factors other than telomerase also act to modulate telomere length. Fluctuations in telomere length in telomerase-positive immortalized cells may contribute to chromosomal instability and clonal evolution.

Cell Transformation, Neoplastic↗

PubMed1999

Plasmodium falciparum: population genetic analysis by multilocus enzyme electrophoresis and other molecular markers.

Abderrazak, S. B., Oury, B, Lal, A. A., Bosseno, M.-F., Force-Barge, P., Dujardin, J.-P., Fandeur, T., Molez, J.-F., Kjellberg, F., Ayala, F. J., and Tibayrenc, M. 1999. Plasmodium falciparum: Population genetic analysis by multilocus enzyme electrophoresis and other molecular markers. Experimental Parasitology 92, 232-238. The population structure of Plasmodium falciparum, the agent of malignant malaria, is uncertain. We have analyzed multilocus enzyme electrophoresis (MLEE) polymorphisms at 7-12 gene loci in each of four populations (two populations in Burkina Faso, one in Sudan, one in Congo), plus one "cosmopolitan" sample consisting of parasite cultures from 15 distant localities in four different continents. We have also performed random amplified polymorphic DNA analysis (RAPD) and restriction fragment length polymorphism (RFLP) and characterized gene varia tion at four antigen genes in the Congo population. All genetic assays show abundant genetic variability in all populations analyzed. With the isoenzyme assays, strong linkage disequilibrium is apparent in at least two local populations, the Congo population and one population from Burkina Faso, as well as in the cosmopolitan sample, and less definitely in the other Burkina Faso population. However, no linkage disequilibrium is detected in the Congo population with the molecular assays. We failed to detect any nonrandom association between the different kinds of genetic markers; that is, MLEE with RAPD or RFLP, RAPD with RFLP, and so on. Although isoenzyme data show statistical departures from panmictic expectations, these results suggest that in the areas under survey, P. falciparum populations do not undergo predominant clonal evolution and show no clear-cut subdivisions, un like Trypanosoma cruzi, Leishmania sp., and other major parasitic species. We discuss the epidemiological and taxonomical significance of these results.

Animals↗

PubMed1996

Human immunodeficiency virus replication in the presence of antiretroviral drugs: analogies to antineoplastic drug resistance.

There are many analogies between antineoplastic therapy and antiviral therapy. For each there may be sanctuary sites in which the drug is ineffective because of decreased accumulation of the active form of the drug or increased competition by naturally occurring inhibitors. These sanctuaries may be restricted to anatomic or biochemical subsets of the population. A knowledge of these sanctuaries is essential to an understanding of the failure of therapy and for the design of more effective treatments. Eradication of these sanctuary sites may be important because they may be responsible for the viral replication or tumor cell division that continues to generate the diversity that drives clonal evolution. Ultimately, diversity as a consequence of the accumulation of mutations results in the selection of resistant viral or tumor cell variants and the failure of drug therapy. Maximizing therapy in an attempt to diminish the rate of generation of this diversity may result in better clinical outcomes, including a delay in the generation of variants with genetic drug resistance.

Antineoplastic Agents↗

PubMed2000

Eradication of Helicobacter pylori and stability of remissions in low-grade gastric B-cell lymphomas of the mucosa-associated lymphoid tissue: results of an ongoing multicenter trial.

The normal human stomach is devoid of any organized lymphatic tissue. Acquisition of mucosa-associated lymphatoid tissue (MALT) in the stomach is considered to be a direct consequence of chronic infection with Helicobacter pylori. Thus, MALT appears to be part of the host defense against the pathogen H. pylori. Consequently, lymphomas arising from gastric MALT may be seen as an end point of a clonal evolution starting from the infection. Cumulative data from several studies show that eradication of H. pylori induces complete histologic remissions in about 70%-80% of the patients. Here we present data of an extended analysis of an ongoing multicenter trial. Eighty-four patients with low-grade gastric MALT lymphoma in stage EI were treated using a dual regimen to eradicate H. pylori. Complete remission was observed in 68 (81%) patients; a partial remission was found in seven (8%) patients. In contrast, nine (11%) patients revealed "no change" and were referred for alternative treatment strategies. The majority of these cases were found to harbor high-grade lymphomas in deeper mucosal areas. Polymerase chain reaction (PCR) performed on the VDJ rearrangements of the immunoglobulin heavy chain yielded monoclonal bands in 50 of 65 analyzed patients (77%) at diagnosis. Interestingly, in patients analyzed during follow up after achieving complete histologic remission, ongoing PCR monoclonality was found in 19 of 39 eligible patients (49%). Several patients who developed local relapse of the lymphoma were found in the group with ongoing PCR monoclonality. Together with data from the literature, these results suggest that the majority of low-grade gastric MALT lymphomas in stage EI respond to eradication of H. pylori. Longer follow-up investigations are necessary to determine whether remissions really indicate a cure from the disease and to elucidate whether PCR monoclonality after complete histological remission is predictive of increased relapse rate.

Anti-Bacterial Agents↗

PubMed1996

Molecular and cellular biomarkers for field cancerization and multistep process in head and neck tumorigenesis.

One way to explain the development of head and neck cancer is through the theories of field cancerization, i.e., the exposure of an entire field of tissue to repeated carcinogenic insult, and multistep process, i.e., development of multiple cancers in a predisposed filed through a series of recognizable stages. Recent molecular genetic studies of histologically normal and premalignant epithelia of high-risk subjects and studies of malignant tumors in aerodigestive tract epithelia have identified a continuum of accumulated specific genetic alterations that possibly occur during the clonal evolution of tumors, namely, during the multistep process. Second primary or multiple primary tumors arise in the same fields as independent clones, with similar but unique molecular genetic and/or cellular alterations. Consequently, the assessment of these genetic and phenotypic alterations has been integrated into clinical chemoprevention trials in an effort to identify biomarkers that are also risk predictors and intermediate end points. This review covers candidate biomarkers of the processes of field cancerization and multistep tumor development in aerodigestive tract epithelia, including general and specific genetic markers, proliferation markers, and squamous differentiation markers.

Biomarkers, Tumor↗

PubMed1992

DNA ploidy of primary hepatocellular carcinoma and pulmonary metastases.

To better comprehend the differences in deoxyribonucleic acid (DNA) content between a primary hepatocellular carcinoma (HCC) and pulmonary metastatic nodules, tissue specimens taken at autopsy of 25 patients who had not received any drugs to treat the malignancy were examined using microspectrophotometry. The DNA distribution patterns were classified into Types I-III, and low (Types I and II) or high (Type III) ploidies, according to DNA distribution. Changes in the DNA content from high to low ploidies, namely DNA ploidy reduction from the primary lesion to pulmonary metastatic lesions, was evident in 9 of the 25 patients (36%), and changes from low to high were noted in 2 of the 25 patients (8%). The remaining 14 (56%) showed no evidence of changes in the DNA ploidy pattern. Reduction of DNA ploidy seen in HCC and its metastatic lesions in the lung may be one of the aspects of clonal evolution or selection mechanisms during the progression of tumor growth and metastasis.

Autopsy↗

PubMed1977

Comparative cytogenetic and histologic studies on early malignant transformation in mesothelial tumors of the ovary.

Comparative cytogenetic and histologic studies on 18 mesothelial ovarian tumors revealed a normal chromosome complement in benign lesions, and the well-known cytogenetic pattern in cystadenocarcinomas. But all borderline tumors of the series evidenced an abnormal stem line and a more or less marked tendency to polyploidization. Serous papillary cystadenomas of this group showed in five out of six cases a stem line with the karyotype 47,XX+C10 (identified by Q-banding), present in both sides of bilateral lesions. It is evidenced that malignant change on the chromosomal level precedes histologically detectable features of malignancy. Histologic equivalents appeared, when the abnormal cell line was established. The initiation of malignant transformation therefore may be signalized by karyotype abnormalities before structural changes can be detected in the corresponding histologic specimens. The results discussed include the concepts of multicentric origin and clonal evolution of malignancy.

Cell Transformation, Neoplastic↗

PubMed1976

Editorial: Chromosomes and human neoplasms. Achievements using new staining techniques.

Numerical and structural chromosome aberrations are frequently found in neoplastic cells. As demonstrated by the new chromosome banding techniques these aberrations are not random, but tend to show a specific occurrence. A model example is the leukemias where many cytogenetical investigations have been done to date. In leukemia chromosome analysis serves the following purposes: to identify a neoplastic process, to confirm and strengthen the hematological diagnosis, for the early diagnosis of transformation from a chronic leukemia into its blastic phase and for following up the clonal evolution of a leukemic cell line. In the discussion of chromosomes and neoplasms it must be mentioned that individuals demonstrating chromosomal instability and some trisomic patients show a greater tendency toward the development of a malignancy. Malignancy is primarily a cellular phenomenon caused by a disturbance in cellular regulation, whose fine events are not known. Therefore the exact role of the chromosomes in neoplastic processes cannot be stated. From experimental investigations it appears that the affected chromosomes carry cell growth regulating factors and also that a specific aberration is the result of the action of a specific agent.

Acute Disease↗

PubMed1993

Escape from negative regulation of growth by transforming growth factor beta and from the induction of apoptosis by the dietary agent sodium butyrate may be important in colorectal carcinogenesis.

There are a number of lines of evidence suggesting that transforming growth factor beta (TGF beta) has an important role in the control of intestinal growth and differentiation. In vivo localization studies show that TGF beta expression occurs predominantly in the differentiated non proliferating cells of the intestinal epithelium. The use of an antisense expression vector for TGF beta resulted in an increased tumorigenicity in an antisense-transfected cancer cell line. In vitro proliferation studies showed colorectal premalignant adenoma cells to be more sensitive to the growth inhibitory effects of TGF beta than colorectal cancer cells. Furthermore the conversion of an adenoma to a carcinoma was accompanied by a reduced response to the inhibitory effects of TGF beta. The acquisition of partial or complete resistance to the inhibitory effects of TGF beta may be an important late event in colorectal carcinogenesis. Of further interest is the possibility that clonal selection could occur even more rapidly in colorectal tumour cells which not only had lost response to TGF beta inhibition but produced TGF beta and were growth stimulated by it. This could have the advantage of not only inhibiting the growth of surrounding less malignantly advanced cells but of also escaping from their potential growth suppressive influence. Carcinogenesis is not, however, simply losing response to negative regulators of growth; the fully malignant cell has to acquire new characteristics of invasiveness and metastatic potential. Growth factors including TGF beta may have a role in the complex cascade of events leading to the activation of proteolytic enzymes which are involved in progression to an invasive phenotype. Cell proliferation in the large bowel, as well as being under the control of endogenous growth factors, is also under the influence of dietary components in the lumen such as the naturally occurring fatty acid sodium butyrate. Sodium butyrate at physiological concentrations induces apoptosis (programmed cell death) in colonic tumour cell lines. Since sodium butyrate occurs naturally in the colorectum, being produced by bacterial fermentation of dietary fibre, it may be involved in the control of cell death in human colorectal epithelium. This could, in part, explain the apparent protective effects of dietary fibre. Clonal evolution and tumour progression in colorectal carcinogenesis could therefore involve loss of response to endogenous growth factors such as TGF beta and an escape from the induction of programmed cell death by dietary factors.

Apoptosis↗

PubMed1995

Kinetics of minimal residual disease during induction/consolidation therapy in standard-risk adult B-lineage acute lymphoblastic leukemia.

We have compared the kinetics of minimal residual disease (MRD) by simultaneous polymerase chain reaction (PCR) monitoring with oligonucleotides for the immunoglobulin heavy chain (IgH) complementarity-determining region 3 (CDR3) and the T-cell receptor gamma chain gene (TCR gamma), as well as clone-specific CDR3 sequences in adult patients (aged 17-51 years) with acute lymphoblastic leukemia (ALL) who entered a complete hematological remission (CR) after chemotherapy with the German multicenter ALL (GMALL) protocol. The sensitivities were one in 10(2-3) for the CDR3- and TCR gamma-PCR and one in 10(5-6) for a two-step, seminested CDR3/clone-specific PCR. At diagnosis, 7/7 patients were CDR3 positive and four were TCR gamma positive in their bone marrow (BM). At the end of induction therapy (after 2 months) 4/6 tested positive for CDR3, 2/6 for TCR gamma, and 5/6 for clone-specific rearrangements. At the end of consolidation treatment (after 7 months) only 1/7 remained positive for CDR3, 2/7 for TCR gamma, and 5/7 for clone-specific rearrangements. After an observation period of 18-36 months, 4/7 patients were still in CR and all were PCR negative by the clone-specific method during or after maintenance therapy. Two patients died in leukemic relapse; one patient relapsed but is still alive. All three of these patients remained PCR positive throughout the course of their disease. Clonal evolution in the IgH locus was found in one of these patients. We conclude that the molecular response to chemotherapy in adult B-lineage ALL is slow, even in patients without risk factors other than age. As in childhood ALL, most patients with long-term CR convert to PCR negativity approximately 18 months after the start of chemotherapy. The data also suggest the existence of early clone-specific PCR negativity in a small proportion of long-term survivors. The predictive value of this observation will now have to be confirmed in a larger study.

Adolescent↗

PubMed1991

Typing of methicillin resistant and susceptible Staphylococcus aureus strains by ribosomal RNA gene restriction patterns using a biotinylated probe.

Nine methicillin-sensitive (MSSA) and 37 methicillin-resistant (MRSA) Staphylococcus aureus isolates of various phage types and resistotypes from seven countries were investigated. Chromosomal DNA was restricted with HindIII or EcoRI, Southern blotted and hybridised with a cDNA probe to 16S+23S rRNA derived from MRSA NCTC 10442. Resulting rDNA profiles could be differentiated on the basis of 22 patterns which were unaffected by changes in plasmid, transposon, enterotoxin A or phage content. Percentage similarity values were calculated using the Dice coefficient and UPGA clustering. Australian and epidemic (EMRSA-1) isolates from the UK showed a high degree of similarity, but the pattern was not unique and was also found in MSSA and other MRSA, e.g. NCTC 10442. An MSSA of phage group II was the most distinct isolate. The method shows potential as an additional tool in a complex typing system, types non-phage typable strains and may provide clues to the clonal evolution of MRSA and MSSA.

Bacterial Typing Techniques↗

PubMed1978

Cytogenetic patterns in acute nonlymphocytic leukemia.

Analysis of chromosomal banding patterns in acute nonlymphocytic leukemia (ANLL) reveals that approximately 50% of patients have an abnormal karyotype. Although there is substantial variability, certain nonrandom abnormalities occur, e.g., +8, -7, and the 8;21 translocation (often accompanied by loss of an X or Y chromosome). The 15;17 translocation appears to be highly specific for acute promyelocytic leukemia. These abnormalities usually are not seen in remission, but reappear in relapse, sometimes exhibiting further clonal evolution; a +8 is the most frequently observed evolutionary change. Patients with ANLL following treatment of a malignant lymphoma tend to have hypodiploid modal numbers and frequently show loss of a chromosome No. 5 or No. 7.

Acute Disease↗

PubMed1978

Cytogenetics of chronic T cell leukemia, including two patients with a 14q+ translocation.

Chromosome studies were done on 7 patients with chronic T cell leukemia. Their lymphocytes responded in culture to one or more T cell mitogens: PHA, Con A, or the calcium ionophore A23187. Clones of cytogenetically-abnormal cells were present in all seven patients, but on occasion the frequency of such cells varied greatly in cultures stimulated with different mitogens. There was no consistent chromosome change, but alterations of chromosome 2 were noted in four individuals and of chromosome 14 in three. In two patients, there was a translocation to the long arm of chromosome 14, producing a 14q+, with the break point in the terminal portion, an abnormality previously observed in B cell lymphomas. One of these patients also showed evidence of clonal evolution in sequential cytogenetic studies, but more data are needed to determine whether such investigations are of prognostic value with respect to the clinical course of the disease.

Adult↗