Objectives This review is to explore whether potential gene interactions in the cell cycles of gametes, zygotes, and embryonic stem (ES) cells are associated with the development of cancer. Methods MEDPILOT at the Central Library of the University of Cologne, Germany (Zentralbibliothek Köln) that covers 5,800 international medical journals and 4,300 E-journals was used to collect data. The initial searches were done in December 2012 and additional searches in October 2013–May 2015. The search terms included “cancer development,” “gene interaction,” and “ES cells,” and the time period was between 1998 and 2015. A total of 147 articles in English language only were included in this review. Results Transgenerational gene translation is implemented in the zygote through interactions of epigenetic isoforms of transcription factors (TFs) from parental gametes, predominantly during the first two zygote cleavages. Pluripotent transcription factors may provide interacting links with mutated genes during zygote-to-ES cell switches. Translation of post-transcriptional carcinogenic genes is implemented by abnormally spliced, tumor-specific isoforms of gene-encoded mRNA/non-coding RNA variants of TFs employing de novo gene synthesis and neofunctionalization. Post-translationally, mutated genes are preserved in pre-neoplastic ES cell subpopulations that can give rise to overt cancer stem cells. Thus, TFs operate as cell/disease-specific epigenetic messengers triggering clinical expression of neoplasms. Conclusion Potential gene interactions in the cell cycle of gametes, zygotes, and ES cells may play some roles in the development of cancer.

This review focuses on gene transcription patterns of leukemogenic S-phases in mitotic cell cycles for identification of enzymatic reactions as potential targets for epigenetics-based drug therapy. Transcription of leukemic genes is triggered by reprogrammed transcription factors (TFs) mediated by chromatin histones. Reprogrammed TFs originate from transcriptional alterations of CpG methylation patterns of mutated epigenetic genes. They preserve memory information of earlier leukemogenic exposures, even transgenerationally via the zygote, through small (e. g. pi) RNA transmitted between cells by exosomes. Normally, reprogrammed TFs are enzymatically silenced and stored as markers in heterochromatic domains. Failure of intra S-phase surveillance (IS) permits the formation and continual operation of DNA replication forks in spite of persisting genotoxic stress. Silenced TFs are re-activated by euchromatin, most likely through leakages of insulator barriers of cis-regulating chromatin modulators (CRM) that normally separate hetero- from euchromatin domains. During transport by sliding nucleosomes, reprogrammed leukemogenic TFs are misplaced at transcription factor binding-/starting-sites (TFBS /TSS) allowing them to interact with and trigger replication of mutated leukemic genes.In conclusion: Interactions of enzymatically reprogrammed TFs, transcribed from mutated epigenetic genes, with replicating leukemic genes at TFBS/TSSs are key driving forces in leukemogenesis. Probably, epigenetic genes, although mutated, still retain their control of replication of leukemic genes. Epigenetics-based enzyme inhibitors must target reprogrammed TFs. Prudently, therapeutic corrections should be introduced within the frame of conventional, cytoreductive treatment protocols. Alternatively, reprogrammed TFs could be replaced by cell populations with regular TF production. Clinically, classification of leukemias should be based on their epigenetic presentation.

Objectives. Processing of epigenomic transcriptional information by cell cycle phase G, and decision-making at checkpoint G(1)/S are the final organizational steps preceding gene replication in transcriptional reorientation programs (i.e., switches from proliferation to cycle arrest and neoplastic transformation). Further analyses of cycle progression will open up new approaches in antineoplastic therapy.Materials and Methods. The following bibliographic databases were consulted: Central Medical Library Cologne, PubMed (English), the last search was done on April 23,2008 and key words searched were: cell cycle, cell memory, DNA methylation, embryonal/neoplastic stem cells, enzyme-modulated chromatin, G(1)-G(1)/S checkpoint, genomic/epigenomics, genomic viral DNA, histones, telomere/telomerases, transcription factors, neoplastic transformation, senescence.Results. Gene transcription and epigenomic surveillance form a functional entity. In proliferation programs, transcriptional information is mediated by chromatin and DNA methylation, analyzed and processed in G, phase, and converged on the parental checkpoint G(1)/S for final decision-making on DNA replication. Genomic reorientation appears to be associated with transcriptional instability, which normally is corrected, possibly during the G(2)/M phase, to new levels of epigenomic equilibria. We speculate that daughter stem cells inherit persistent neoplasm-specific transcriptional instabilities through failure of the parental G(1)/S checkpoint. Foreign, silenced, potentially oncogenic DNA sequences, i.e. regular components of the human genome such as endogenous retroviruses, could conceivably be activated for expression in neoplastic transformation by epigenomic histone deacetylase/acetyl transferase/histone methyltransferase-mixed lineage leukemia deregulations.Conclusions. Failure of cell cycle G(1)/S decision-making for DNA replication is the final and possibly a major cause in neoplastic transformation. Therefore, further analysis of the dynamics of G(1)-G(1)/Sphases could provide new opportunities for therapeutic strategies. (c) (c) 2008 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.

Cell dedifferentiation occurs in different cell systems. In spite of a relative paucity of data it seems reasonable to assume that cell dedifferentiation exists in reversible equilibrium with differentiation, to which cells resort in response to intercellular signals. The current literature is indeed compatible with the concept that dedifferentiation is guided by structural rearrangements of nuclear chromatin, directed by epigenetic cell memory information available as silenced genes stored on heterochromatin, and that gene transcription exists in reversible "fluctuating continua" during parental cell cycles. Here, we review the molecular mechanisms of cell dedifferentiation and suggest for hematopoietic development that postnatal hemangioblasts are generated by dedifferentiation of committed hematopoietic stem cells.

Abstract:  Reducing the blood supply of tumors is one modality to combat cancer. The objective of this study was to evaluate such an approach in the treatment of localized murine AML (acute myelogenous leukemia). For this purpose we designed an experimental model in which leukemic cells were embedded in 1% agar discs before subcutaneous implantation in C57Bl female mice. The C‐1498 AML cell line (Frederick Inst., NCI, MD, USA) was used. Thirty experimental mice received on alternate days injections of 5 × 2.5 μg anti‐VEGF (vascular endothelial growth factor) and 5 × 2.5 μg anti‐Flk‐1 (VEGFR2) antibodies to the site of cell implantation over a period of 10 d. Fifteen control mice received daily PBS injections. All mice were sacrificed 16 d after AML implantation. Of the 30 experimental animals, macroscopic examination showed in 21 animals (70%) small sized, pale tumors (0.5 g); in six mice (20%) the tumors were replaced completely by necrotic tissue, while in three mice (10%), there were large (2.5 g), highly vascularized tumors. In all 15 control mice large highly vascularized tumors were seen. A separate group of mice was studied for total survival following AML implantation. While 12 mice in the control group not treated with antibodies survived for 16 d post‐implantation, survival was prolonged in 15 antibody treated mice by approximate 30 d to a total survival time of 48 d. Tumor specimens were processed for histology, immunohistochemistry (IHC) for CD31 endothelial cell antigen, and tube‐like formation assay. The small, pale tumors of antibody treated animals consisted of degenerate hyaline material with remnant nests of leukemic cells, whereas large tumors showed sheets of leukemic cells and numerous blood vessels. Specimens processed for CD31 antigen showed scarce or absence of blood vessels in the small, pale tumors in contrast to intensive staining from a rich network of blood vessels in the large, highly vascularized tumors. Tube‐like formation assays disclosed rudimentary Grade 1 endothelial cell tubes in the small, pale tumors as opposed to polygonal Grade 4 tube formation in control animals. In conclusion, this murine model of localized AML allows assessment of anti‐angiogenic tumor regression. Anti‐angiogenic antibodies against VEGF and Flk‐1 have therapeutic effects in murine AML.

The life-long interdependencies/interactions between hemato- and endotheliopoiesis suggest that they form a supplementary functional entity. This view is compatible with the concept of stem cell plasticity as a reversible continuum and is substantiated by the common hematopoietic-endothelial stem cell, i.e., hemangioblasts, with bidirectional, reversible gene transcription and persistence in postnatal life. Indeed, embryonal stem cells/hemangioblasts appear to form a reservior in the adult with the possibility of dedifferentiation of more differentiated progenitor cells back to hemangioblasts. The recent detection of BCR/ABL fusion proteins in endothelial cells during vascular neoangiogenesis in CML suggests that endothelial cells are part of the neoplastic clone, and extends the concept of a functional entity to include CML angiogenesis. Thus, hemangioblasts rather than committed hematopoietic stem cells appear to be target cells for the first oncogenic hit in CML, which could occur as early as during the first steps of embryonal stem cell differentiation towards hemato-endotheliopoiesis and/or in hemangioblasts persisting in adults. The relation of the other leukemias to hemangioblasts is not known.

Embryonal stem (ES) cells are the earliest ontogenetically identifiable stem cells of the embryo proper for all subsequent mesenchymal stem cells and for highly specialized differentiated cells. This review characterizes, in a working hypothesis, the role of reversible EMT/MET (epithelialmesenchymal transition) as a manifestation of cell plasticity 1) in the development of ES cells to adult stem cells (hematopoietic stem cells) and 2) in metastasizing cancer cells. Animal studies support the concept that EMT/MET is a key manifestation of cell plasticity in the development of ES cells to adult stem cells, and in conversion of localized to metastasizing cancer cells. In fact, ES cells may persist to postnatal life, in cytologically verifiable form and/or within the frame of EMT/MET, as ultimate reservoir for adult stem cells. Furthermore, EMT could possibly serve as a conceptional link between physiologic and pathologic signaling pathways. Clonal confirmation in humans is necessary.

Epithelial mesenchymal transitions are a remarkable example of cellular plasticity. These transitions are the hallmark of embryo development, are pivotal in cancer progression, and seem to occur infrequently in adult organisms. The reduced incidence of transitions in the adult could result from restrictive functions of the microenvironment that stabilizes adult cell phenotypes and prevents plastic behavior. Multipotential progenitor cells exhibiting a mesenchymal phenotype have been derived from various adult tissues. The ability of these cells to differentiate into all germ layer cell types, raises the question as to whether mesenchymal epithelial transitions occur in the adult organism more frequently than presently appreciated. A series of cytokines are known to promote the transitions between epithelium and mesenchyme. Moreover, several transcription factors and other intracellular regulator molecules have been conclusively shown to mediate these transitions. However, the exact molecular basis of these transitions is yet to be resolved. The identification of the restrictive mechanisms that prevent cellular transitions in adult organisms, which seem to be unleashed in cancerous tissues, may lead to the development of tools for therapeutic tissue repair and effective tumor suppression.

Although myelodysplasia in adults has been well defined by the FAB group, direct translation of this categorisation to children has been controversial. Consequently, in order to better outline the natural history of the disease, a retrospective analysis of case reports and series published in the English language between 1982 and 1996 of. patients with MDS aged between one day and 16 years was undertaken. The diagnosis and the FAB grouping as outlined in the publications were accepted. Two hundred and sixty patients were described in 19 publications. The median presentation age was 5.43 (mean 3.5, SD 4.83) years and 87 were female. In 16, family history of a related haematological derangement was elicited, while in 42, constitutional alterations were described. Organomegaly was reported in 113 patients. The mean Bournemouth score was 2.51 (SD 1.01). Cytogenetic anomalies were detected in 82/203. Progression of the diagnosis to AML (n=47), RAEB (n=11) or RAEB-T (n=3) was noted in 61, while spontaneous regression was observed in two. Survival was significantly higher in those undergoing BMT (41% of 73) compared to those who received first line induction therapy for acute myeloid leukaemia (11% of 19; p= 0.01) or those managed with supportive means only (24%; p= 0.01). Intensive chemotherapy did not improve the rate or length of survival. Refractory anaemia was diagnosed in 68, while in seven, the hypoplastic variant was described. Here, constitutional abnormalities were noted in a higher proportion (23; p= 0.08). Patients with raeb-t (n=41) were older (mean age 8.71 SD 4.65; p= 7.7 E-5), had a significantly higher Bournemouth score (3.1, SD 0.76; p= 7 E-4) and blood blast number (7.2% SD 6.14; p= 6.3 E-6). Cytogenetics were abnormal in 16/25 and in seven, this derangement involved chromosome 7. Within this group, the disease progressed to AML in 17. Patients with RARS (n=14) were typically female (p= 0.0001), was in association with Pearson's disease in two, and commonly had cytogenetic abnormalities (p= 0.005). Children with CMML (n=60) were the youngest (mean age 2.91 SD 3.3 years; 1 p=0.0001), had a significantly higher incidence of organomegaly(n=52, p= 1 E-6), and prevalence of cytogenetic abnormalities (22/41; p= 0; related to chromosome 7 in 12) than the rest of the population, and seven progressed to AML. Features of JCML were reported in 38, and this diagnosis predominated among younger boys who had higher Hb F levels (mean 30.75% SD 14.23 vs. mean 7.14%, SD 6.48, p=0.00001.6) and blood blast cell counts (13 percent, SD 30.8; p= 0.003). Twenty three patients had abnormalities that involved chromosome 7. Morphologically, five were RA, six RAEB, three RAEB-T and nine CMML. In patients not receiving a BMT, survival was significantly shorter in those with RAEB-T and JCML (mean 0.71, SD 4.65; p=-.0001 and 2.94, SD 1.37 years, p= 0.001) and of less than two years in all. Forty-one percent of patients with RA were surviving at the time of publication. Children with CMML, RARS and RAEB had an intermediate survival with a small proportion alive in the long term. Among those with abnormalities involving chromosome 7, survival was heterogeneous and closely followed their FAB type. We conclude that patients with CMML and JCML disorders behave differently, that chromosome 7 disorders are heterogeneous, and that intensive chemotherapy is no better than supportive measures.

In this review we summarize data on the human gut mucosa associated lymphatic tissues as part of the common mucosal immune system. Its embryonal-fetal and post-natal ontogeny becomes severely distorted and compromised by mal-/undernutrition which is so prevalent in developing countries. Pathogenetic interdependencies exist between maternal-fetal undernutrition, the ontogeny of the immune system, constant antigenic stimulation of the mucosal immune system post-natally, and the 14 million deaths annually from infections in children below the age of 5 years in developing countries. A detailed knowledge of these interdependencies is required for effective prevention and treatment in an attempt to reduce the high morbidity and mortality rates of children in developing countries.

We have studied the survival of clonogenic neoplastic cells of a murine pre-B-lymphoma (BCl-1) of the spleen in culture. We have found quantitative deficiencies such as reduced surface adherence of stromal cells and impaired CFU-F (colony forming units-fibroblast) and pre-CFU-F colony and layer formation in stromal cultures of lymphoma bearing spleen, as compared to cultures from normal spleen. There are two populations of clonogenic BCl-1 lymphoma cells surviving in culture: one population is surface adherent, and the other is non-adherent. Both populations transmit the lymphoma to healthy indicator mice. We hope that this model will be helpful in studying minimal residual leukemic disease [1] in culture.

CancerVolume 70, Issue 4 p. 902-903 CorrespondenceFree Access Acute undifferentiated leukemia with CD7+ and CDI3+ immunophenotype Gregor Prindull M.D., Gregor Prindull M.D. Department of Pediatrics University of Gottingen GermanySearch for more papers by this author Gregor Prindull M.D., Gregor Prindull M.D. Department of Pediatrics University of Gottingen GermanySearch for more papers by this author First published: 15 August 1992 https://doi.org/10.1002/1097-0142(19920815)70:4<902::AID-CNCR2820700431>3.0.CO;2-9AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1 Bassan R, Biondi A, Benvistito S, et al. Acute undifferentiated leukemia with CD7+ and CD13+ immunophenotype. Cancer 1992; 69: 396– 404. 2 Pittaluga S, Raffeld M, Lipford EH, et al. 3Al(CD7) expression precedes T β gene rearrangements in precursor T (lymphoblastic) neoplasms. Blood 1986; 68: 134– 9. 3 Vodinelich L, Tax W, Bai Y, et al. A monoclonal antibody (WTI) for detecting leukemias of T-cell precursors. Blood 1983; 62: 1108– 13. 4 Hara J, Yumura-Yagi K, Tawa A, et al. Molecular analysis of acute undifferentiated leukemia: two distinct subgroups at the DNA and RNA levels. Blood 1989; 74: 1738– 46. 5 Kurtzberg J, Denning S, Le P, et al. Biology of the normal and leukemic CD7+ stem cell. J Cell Biol 1987; (Suppl 11A): 235. 6 Haynes BF, Martin ME, Kay HH, et al. Early events in human T-cell ontogeny. Phenotypic characterization and immunohistologic localization of T-cell precursors in early human fetal tissues. J Exp Med 1988; 168: 1061– 80. 7 Lobach DF, Hensley LL, Ho W, et al. Human T-cell antigen expression during early stages of fetal thymic maturation. J Zmmunol 1985; 135: 1752– 9. 8 Campana D, Janossy G, Coustan-Smith E, et al. The expression of T-cell receptor-associated proteins during T-cell ontogeny in man. J lmmunol 1989; 142: 57– 66. 9 Uckun FM. Regulation of human B-cell ontogeny. Blood 1990; 76: 1908– 23. 10 Greaves MF. Etiology of childhood acute lymphoblastic leukemia: a soluble problem? In: RP Gale, D Holzer, editors. UCLA Symposium on Cellular Biology, New Series 108. New York: Allan Liss, 1990: 1– 14. 11 Prindull G. Early embryonal/fetal lymphopoietic ontogeny and leukemogenesis. Ann Hematol 1991; 63: 291– 6. Volume70, Issue415 August 1992Pages 902-903 ReferencesRelatedInformation

Paediatric oncology in developing countries is a speciality in its own right that has so far been largely neglected by the western medical profession. It has specific features of genetic cancer predisposition and of external factors influencing phenotypic cancer manifestations. We point out here some of the specific features of cancer presentation in children of developing countries.

Acute myeloid leukemia (AML) was induced in C57Bl mice through the i.v. innoculation of C-1498 cell line. One week later, i.e. at mid-term disease, the leukemic mice received an i.p. injection of 200 ng rmGM-CSF and 24 h later, two consecutive i.p. cytosine arabinoside (ara-C) injections at 6 h intervals (2 x 200 mg/kg). The leukemic mice received 3-4 weekly courses of combined therapy and survived 4-5 weeks following leukemia induction. Control mice received ara-C only and survived 2-3 weeks. Moreover, leukemic mice administered both GM-CSF and ara-C had a lower marrow leukemic load than mice treated with ara-C only. From these findings, we conclude that therapy of murine AML with combined rmGM-CSF and ara-C is more effective than ara-C only. Leukemic mice treated with GM-CSF and ara-C had a longer life expectancy and a smaller leukemic load than mice administered ara-C only.