View details for DOI 10.1056/NEJMoa1506597, View details for Web of Science ID 000368404800006, View details for PubMedCentralID PMC4784450. Reitz, M. S., Mann, D. L., Eiden, M., Trainor, C. D., Clarke, M. F. METHYLATION OF HUMAN T-CELL LEUKEMIA-VIRUS PROVIRAL DNA AND VIRAL-RNA EXPRESSION IN SHORT-TERM AND LONG-TERM CULTURES OF INFECTED-CELLS. FUKUNAGAJOHNSON, N., Ryan, J. J., Wicha, M., Nunez, G., Clarke, M. F. OVEREXPRESSION OF BCL-X(S), SENSITIZES MCF-7 CELLS TO CHEMOTHERAPY-INDUCED APOPTOSIS. Similarly, tumors contain a minority population of cancer stem cells that maintain the tumor. Gene profiling experiments have revealed similarities between cancer and embryonic stem (ES) cells. These studies suggest that adenovirus suicide vectors may provide a simple and effective method to selectively eliminate cancer cells derived from epithelial tissue that contaminate bone marrow to be used for autologous BMT. View details for Web of Science ID A1991GR93700016. He was the Director General of the Royal United Services Institute from 2007 to 2015, having previously been Professor of Defence Studies at King's College London since 1995. Chandhasin, C., Yoo, S., Del Rosario, J., Chen, Y. K., Stafford, J., Perabo, F., Clarke, M. F. Depletion of Trp53 and Cdkn2a Does Not Promote Self-Renewal in the Mammary Gland but Amplifies Proliferation Induced by TNF-. Replication-deficient viral vectors are currently being used in gene transfer strategies to treat cancer cells. T-cell lines established from human T-cell leukemia-lymphoma virus associated T-cell neoplasias, in contrast to the T-cell acute lymphocytic leukemia cell lines, expressed both DR antigens and DR alpha mRNA; the HpaII sites within the BglII fragment of DR alpha DNA of these human T-cell leukemia-lymphoma virus-positive T-cell lines were in all cases at least partially unmethylated. Thus, the predicted transforming product, a protein of 27,281 daltons, may be the actual precursor for normal human platelet-derived growth factor chain A. The regulation of hematopoietic stem cell (HSC) homeostasis is not well understood. At the molecular level, Usp16 affects Rspo-mediated phosphorylation of LRP6. Profiles. Recently, various new players that regulate HSC maintenance (e.g. Interestingly, exposure to DMSO leads to an alteration of the protein conformation of the p53 mutant to one recognized by a wild-type specific monoclonal antibody. This cell line contains a wild-type p53 gene and is an ideal model for studying the mechanism of IR resistance in this disease. We focused our analysis of gene expression on RNA from primitive leukemia-initiating cells, which harbor 5q deletions, and analyzed 12 genes within the CDR that are expressed by normal hematopoietic stem cells. The prognostic power of the IGS was increased when combined with the wound-response (WR) signature.The IGS is strongly associated with metastasis-free survival and overall survival for four different types of tumors. View details for Web of Science ID 000316614600063. Restoration of CTNNA1 expression in HL-60 cells resulted in reduced proliferation and apoptotic cell death. He was Director of the Royal United Services Institute from 2007 to 2015. CD47 is expressed at different levels by neoplastic and normal cells. As well as addressing the patient's medical needs, these highly trained professionals . All of the DR alpha DNA sequences detected by a cloned DR alpha cDNA probe are contained in a BglII fragment which varies slightly in size (4.0 to 4.8 kilobases) from one individual to another. Cells that expressed kappa- or lambda-light chains were separated by cell sorting from kappa- or lambda-negative cells and replaced in culture. In bone marrow, RGS18 level is highest in long-term and short-term hematopoietic stem cells, and is decreased as they differentiate into more committed multiple progenitors. miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway. INGRAHAM, L. M., Weening, R. S., Clarke, M. F., Boxer, L. A., Baehner, R. L. Freeman Spogli Institute for International Studies, Institute for Computational and Mathematical Engineering (ICME), Institute for Human-Centered Artificial Intelligence (HAI), Institute for Stem Cell Biology and Regenerative Medicine, Stanford Institute for Economic Policy Research (SIEPR), Stanford Woods Institute for the Environment, Office of VP for University Human Resources, Office of Vice President for Business Affairs and Chief Financial Officer, Directed Reading in Stem Cell Biology and Regenerative Medicine, Stem Cell Biology and Regenerative Medicine (Phd Program), DOI 10.1146/annurev.cellbio.22.010305.104154. To direct the replication of the virus to breast cancer, we have considered one characteristic present in a great proportion of these cancers, which is the expression of estrogen receptors (ERs). View details for Web of Science ID A1984SJ97500057. A., Stelzer, Y., Luong, A. V., Isobe, T., Zarnegar, M. A., Watanabe, N., Antonana, S., Lam, J., Qian, D., Sikandar, S. S., Kuo, A. H., Heitink, L. S., Shimono, Y., Scheeren, F. A., Cai, S., Hisamori, S., Sahoo, D., Dirbas, F. M., Somlo, G., Jaenisch, R., Christina, C., Clarke, M. F. Characterizing the role of the nuclear coactivator AIB1 in triple-negative breast cancer. and Ph.D. in economics from the University of Kentucky. We assessed tumorigenicity using limiting dilution analysis.KIT and KITLG were expressed heterogeneously by a subset of human colon tumors. [1] Clarke is a former Deputy Vice-Principal and Director of Research Development at King's College London, where he remains a Visiting Professor of Defence Studies. Also, HTLV can be transmitted in vitro to cord blood T-lymphocytes. This increase is associated with the acquisition of long-term reconstitution capacity by cells of the phenotype c-kit+Sca-1+Flt3+CD150-CD48-Lin-, which defines multipotent progenitors in wild-type mice. However, no indomethacin or ETYA inhibition of oxygen utilization was detected in the presence of 1 mM KCN, suggesting that the inhibitable portion of the respiratory burst observed with indomethacin or ETYA was dependent on mitochondrial respiration. View details for Web of Science ID A1982NS41700015, American Association of Physicians, - (-), American Society of Clinical Investigation, - (-), Rackham Award, University of Michigan (-), Please see Dr. Michael Clarke's bio on the following School of Medicine website(s). These results indicate that a basic domain other than the well defined NLS is required for the nuclear import of p53. Paneth cells contribute to the small intestinal niche of Lgr5(+) stem cells. Several pathways, including Wnt signaling, MAP Kinase signaling, and Adherens Junction, are well known for their role in cancer development and stem cell biology. At the time of ABMT, 10 were chemosensitive, four were chemoresistant, and 10 were absolutely refractory to platinum. Up to one-third of the long-term culture initiating cell (LTC-IC) are genetically modified by the culture conditions. Liu, T. X., Becker, M. W., Jelinek, J., Wu, W., Deng, M., Mikhalkevich, N., Hsu, K., Bloomfield, C. D., Stone, R. M., DeAngelo, D. J., Galinsky, I. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Here, we show that LEFTY1, a secreted inhibitor of NODAL/SMAD2 signaling, is produced by mammary progenitor cells and, concomitantly, suppresses SMAD2 and SMAD5 signaling to promote long-term proliferation of normal and malignant mammary epithelial cells. Willingham, S. B., Volkmer, J., Gentles, A. J., Sahoo, D., Dalerba, P., Mitra, S. S., Wang, J., Contreras-Trujillo, H., Martin, R., Cohen, J. D., Lovelace, P., Scheeren, F. A., Chao, M. P., Weiskopf, K., Tang, C., Volkmer, A. K., Naik, T. J., Storm, T. A., Mosley, A. R., Edris, B., Schmid, S. M., Sun, C. K., Chua, M., Murillo, O., Rajendran, P., Cha, A. C., Chin, R. K., Kim, D., Adorno, M., Raveh, T., Tseng, D., Jaiswal, S., Enger, P. O., Steinberg, G. K., Li, G., So, S. K., Majeti, R., Harsh, G. R., van de Rijn, M., Teng, N. N., Sunwoo, J. Professor Clarke is a former Deputy Vice . Finally we report that the TNF-NFKB1 signalling pathway directly regulates CD47 by interacting with a constituent enhancer located within a CD47-associated SE specific to breast cancer. In contrast, AdEHE2F was attenuated in nontransformed quiescent cells growing under normoxic conditions, suggesting that an intact pRB pathway with low levels of E2F transcription factors acts as a negative modulator for the virus. Many of these mutations affect cell proliferation and survival. Tumors injected four times with the bcl-xs adenovirus showed a 50% reduction in size. Adorno, M., Sikandar, S., Mitra, S. S., Kuo, A., Nicolis Di Robilant, B., Haro-Acosta, V., Ouadah, Y., Quarta, M., Rodriguez, J., Qian, D., Reddy, V. M., Cheshier, S., Garner, C. C., Clarke, M. F. Identification of a cKit(+) Colonic Crypt Base Secretory Cell That Supports Lgr5(+) Stem Cells in Mice. A subpopulation of tumor cells, termed cancer stem cells (CSC), appears uniquely able to fuel the growth of phenotypically and histologically diverse tumors. Pulse induction of p53 alone did not affect Shep-1 cell viability, while induction of p53, followed by IR, resulted in cell death and DNA fragmentation proportional to the dose of IR and the level of p53 expression. Critically, we found that only streaming and not random migration of single cells was significantly correlated with proximity to vessels, with intravasation and with numbers of elevated circulating tumor cells in the bloodstream. Hosen, N., Yamane, T., Muijtjens, M., Pham, K., Clarke, M. F., Weissman, I. L. Phenotypic characterization of human colorectal cancer stem cells. Although the existence of mammary stem cells has been suggested by serial transplantation studies in mice, their identification has been hindered by the lack of specific surface markers, and by the absence of suitable in vitro assays for testing stem cell properties: self-renewal and ability to generate differentiated progeny. His writingson justice, ethics, democracy, and markets--have been translated into 27 languages. Regulation of the Wnt pathway in stem cells and primary tissues is still poorly understood. It was found that a single mutation of Arg-306 resulted in the defect of p53 nuclear import. Fundamentally, the system is the paradigm of a complex interactive tissue, in which the proliferation and regulated differentiation of one parenchymal cell type (the hematopoietic stem cell) is governed by the surrounding stromal cells. Enforced expression of miR-142 or miR-150 in normal mouse mammary stem cells resulted in the regeneration of hyperproliferative mammary glands in vivo. PROF. MICHAEL CLARKE (Director, Royal United Services Institute): I think the United States has been behind us in this respect. View details for Web of Science ID A1983RE64300046. A., Clarke, M. F., Quake, S. R. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Hernandez-Alcoceba, R., Pihalja, M., Nunez, G., Clarke, M. F. Molecular cloning and characterization of a novel regulator of G-protein signaling from mouse hematopoietic stem cells. View details for DOI 10.1016/j.cell.2010.09.046, View details for Web of Science ID 000283052200007. View details for Web of Science ID A1991EY27300001. Although cancer cell lines provide invaluable information, their biological properties often differ in crucial ways from de novo cancer cells. The mammary epithelium undergoes several rounds of extensive proliferation during the female reproductive cycle. LONDON Dancer, choreographer, ex-heroin addict, prodigal son, perfectionist, art-world darling, club-world star: Michael Clark was for a long time . . Such cells do not express beta-galactosidase, indicating that hematopoietic stem cells do not express transgene encoded by adenovirus vectors based upon the RSV-AD5 vector system. This functional subset of cancer cells is operationally defined as the "cancer stem cell" (CSC) subset. To see if a limited sampling of tumor tissue from human subjects is a feasible way to gather We discuss possible functional consequences of such nucleosome positioning. These analogues were compared to determine the effect of biotinylation on biological activity and GM-CSF receptor binding characteristics. Shimono, Y., Zabala, M., Cho, R. W., Lobo, N., Dalerba, P., Qian, D., Diehn, M., Liu, H., Panula, S. P., Chiao, E., Dirbas, F. M., Somlo, G., Pera, R. A., Lao, K., Clarke, M. F. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Using single-cell transcriptomic data, we assessed cell-type-specific manifestations of different hallmarks of ageing-such as senescence3, genomic instability4 and changes in the immune system2. Murine RV EW robustly activated type I IFNs and several antiviral genes (IFN-stimulated genes) in the intestine by bulk analysis, the source of induced IFNs primarily being hematopoietic cells. Northstar is a useful tool to assign known and novel cell type and states in the age of cell atlases. The Department of Adolescent and Young Adult Medicine's multidisciplinary team includes adolescent physicians, clinical nurse consultant, social worker, clinical psychologist, occupational therapist, dietitian and experienced ward nurses. Here we show that in Ts65Dn mice, which are trisomic for 132 genes homologous to genes on human chromosome 21, triplication of Usp16 reduces the self-renewal of haematopoietic stem cells and the expansion of mammary epithelial cells, neural progenitors and fibroblasts. View details for Web of Science ID A1986A778300041. A growing body of evidence indicates that subpopulations of cancer stem cells (CSCs) drive and maintain many types of human malignancies. Sumantran, V. N., Ealovega, M. W., Nunez, G., Clarke, M. F., Wicha, M. S. In vitro expansion of hematopoietic cells for clinical application. Woodward, W. A., Bristow, R. G., Clarke, M. F., Coppes, R. P., Cristofanilli, M., Duda, D. G., Fike, J. R., Hambardzumyan, D., Hill, R. P., Jordan, C. T., Milas, L., Pajonk, F., Curran, W. J., Dicker, A. P., Chen, Y. A Quiescent Bcl11b High Stem Cell Population Is Required for Maintenance of the Mammary Gland. Similar to TWF1, VIM also regulates F-actin formation, a key component of cellular transition to a more invasive mesenchymal phenotype. View details for Web of Science ID A1992HP64200009. In this issue of Cell Stem Cell, Hermann et al. View details for DOI 10.1016/j.gde.2003.11.007, View details for Web of Science ID 000188978200008. Furthermore, these approaches are not feasible for primary tumor cells that cannot survive tissue culture conditions or that may change phenotype in rats. However, inferring both the state and direction of differentiation is challenging. Professor Michael Clarke, former director of the defence think tank Rusi said: "Often these symbols will be location-based - they will be communicating where a unit is heading. It is unusual among haemopoietic cell lines in that one of these is c-sis, the gene from which the oncogene v-sis of the simian sarcoma virus was derived, and perhaps the gene for platelet-derived growth factor (PDGF). The human RGS18 ortholog has a tissue-specific expression pattern similar to that of mouse RGS18. These findings demonstrate that p53 overexpression renders Shep-1 cells IR-sensitive and suggest that large quantities of exogenous p53 can overcome the factors inhibiting p53-mediated, IR-induced apoptosis. CHUCK, A. S., Clarke, M. F., Palsson, B. O. bcl-x(s) gene therapy induces apoptosis of human mammary tumors in nude mice. Although initial adhesion of hematopoietic cells was improved by the presence of both ECMs, the overall progenitor and nonadherent cell productivity was not improved nor did the stroma grow to confluency faster. Epithelial-to-mesenchymal transition has been shown to correlate with therapy resistance, but the functional link and signalling pathways remain to be elucidated. Adjunct Professor Michael Whitehouse. Furthermore, because these cells drive tumor development, strategies designed to target this population may lead to more effective therapies. View details for DOI 10.1073/pnas.0610117104, View details for Web of Science ID 000243761100053. Strategies that enhance the activity of ADCC effectors, including NK cells, may improve the efficacy of trastuzumab. Flow cytometry and microfluidics-based single-cell multiplex RT-PCR allowed dissection of IFN responses in single RV-infected and bystander intestinal epithelial cells (IECs). View details for Web of Science ID A1984TC73000037. He is a board certified oncologist with extensive training in molecular biology and stem cell biology. He is a board certified oncologist with extensive training in molecular biology and stem cell biology. In contrast, transplantation of CSC results in changes in the branching patterns of endogenous ducts while non-CSC do not. In approaching the bone marrow culture system, we recognize the critical role that hematopoietic growth factors (HGFs) play in hematopoiesis. George Malcolm (1917-1997), Pianist, Cembalist, Dirigent und Komponist. Jasty, R., Lu, J. Y., Irwin, T., Suchard, S., Clarke, M. F., Castle, V. P. Cooperation of a single lysine mutation and a C-terminal domain in the cytoplasmic sequestration of the p53 protein, A method of limited replication for the efficient in vivo delivery of adenovirus to cancer cells. Hernandez-Alcoceba, R., Pihalja, M., Qian, D. L., Clarke, M. F. Differential gene expression profiling of adult murine hematopoietic stem cells. Usp16 regulation of the Wnt pathway in mouse and human tissues is at least in part mediated by activation of Cdkn2a, a regulator of senescence. Adjunct Senior Lecturer Dr Jan Warnken. View details for DOI 10.1016/j.jviromet.2011.02.015, View details for Web of Science ID 000290836400014, View details for PubMedCentralID PMC3086718, View details for DOI 10.1158/1538-7445.AM2011-1582, View details for Web of Science ID 000209701302286, View details for Web of Science ID 000289796200068. Betancur, P. A., Abraham, B. J., Yiu, Y. Y., Willingham, S. B., Khameneh, F., Zarnegar, M., Kuo, A. H., McKenna, K., Kojima, Y., Leeper, N. J., Ho, P., Gip, P., Swigut, T., Sherwood, R. I., Clarke, M. F., Somlo, G., Young, R. A., Weissman, I. L. Colorectal Cancer Liver Metastasis: Evolving Paradigms and Future Directions. In experiments on nude mice bearing HeLa ascites tumors, intraperitoneal injection of AdRSVlaclys/pE1 resulted in a significantly higher percentage of infected HeLa cells as compared with the PBS controls (p < 0.05) or the AdRSVlaclys/pUC19 controls (p < 0.01). Unfortunately, although chemotherapy and/or radiation therapy can sometimes shrink tumors, metastatic cancers of epithelial origin are essentially incurable. Michael Clarke is a UK academic and "terror expert". Il neo-ateismo ritiene che la superstizione, la religione e l'irrazionalismo non dovrebbero essere tollerati, e si propone di contrastarli . View details for Web of Science ID A1995TE58500016. Professor Clarke was presented by Professor Len Scott from the Department of International Politics. View details for Web of Science ID 000079346200015. Inhibition of TLR2, its co-receptor CD14, or its downstream targets MYD88 and IRAK1 inhibits growth of human breast cancers in vitro and in vivo. Dr Michael Clarke is an internationally recognised expert on the history and politics of the Xinjiang Uyghur Autonomous Region, People's Republic of China (PRC), Chinese foreign policy in Central Asia, Central Asian geopolitics, nuclear proliferation and non-proliferation and American grand strategy and foreign policy. AKR/J mice had significantly higher frequencies and numbers of both HSCs and restricted progenitors in their bone marrow than C57BL/Ka-Thy-1.1 mice. Both KrasG12D -dependent and KrasG12D -independent tumors display a high level of genomic instability, and KrasG12D -independent tumors harbor numerous amplified genes that can activate the MAPK/ERK signaling pathway. Synchronized cells allowed to pass out of G1 prior to being placed at 32.5 degrees C continued to cycle until subsequently arrested in G1; loss of viability occurred following G1 arrest. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. Microarray analysis comparing Thy1+CD24+ tumor cells to not-Thy1+CD24+ cells identified a list of differentially expressed genes. View details for DOI 10.1371/journal.pone.0002428, View details for Web of Science ID 000263280700013, View details for PubMedCentralID PMC2413402, View details for Web of Science ID 000454834700190. The tumors that arose from purified CD44(+) cells reproduced the original tumor heterogeneity and could be serially passaged, thus demonstrating the two defining properties of stem cells: ability to self-renew and to differentiate. In order for treatment to be effective long term, the mechanisms enabling treatment adaptation need to be understood. "Bulk" measurements of antiviral innate immune responses from pooled cells yield averaged signals and do not reveal underlying signaling heterogeneity in infected and bystander single cells. In 2007, he became the Director of the Royal United Services Institute. Control cultures that were exposed to conCM after 4 weeks in culture significantly improved their cell productivity during the latter 4 weeks of culture compared with control. The results indicate that locally produced GM-CSF and IL-3 do augment hematopoiesis for several weeks in culture. Professor Michael Clarke is a Fellow of King's College London. Cancers originally develop from normal cells that gain the ability to proliferate aberrantly and eventually turn malignant. Rapid medium exchanged LTHBMCs were established on surfaces precoated with human natural fibronectin and type 1 rat tail collagen. Chen, E. C., Karl, T. A., Kalisky, T., Gupta, S. K., O'Brien, C. A., Longacre, T. A., van de Rijn, M., Quake, S. R., Clarke, M. F., Rothenberg, M. E. miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway. Purified RGS18 interacts with the alpha subunit of both G(i) and G(q) subfamilies. The metabolic and secretory characteristics of NIH-3T3 fibroblasts transfected with a cDNA encoding human granulocyte-macrophage colony stimulating factor (GM-CSF) were examined as a function of the culture medium exchange schedule. Human T-cell leukaemia virus (HTLV), first isolated in the United States from a patient with cutaneous T-cell lymphoma, is a unique horizontally transmitted retrovirus which is highly associated with certain adult T-cell malignancies. Location University of Rochester 402 Hutchison Hall P.O. The simulation demonstrates that removal of stem cells is a possible mechanism leading to culture decline. Yoo, S., Chandhasin, C., Del Rosario, J. R., Chen, Y. K., Stafford, J., Quake, S., Perabo, F., Clarke, M. F. Pharmacologic characterization of TACH101, a first-in-class KDM4 inhibitor for development as a cancer therapeutic. Conclusions Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice. Publications Journal Articles (89) Conference Papers (5) Journal Articles Clarke, Paul R. (2021). Indomethacin (4 x 10(-4) M) and ETYA (2 x 10(-5) M) did inhibit oxygen utilization and superoxide production. The coordinated downregulation of three microRNA clusters and the similar functional regulation of clonal expansion by miR-200c provide a molecular link that connects BCSCs with normal stem cells. Patients generally die of cancer after the failure of current therapies to eliminate residual disease. In the colon, cKit(+) goblet cells were interdigitated with Lgr5(+) stem cells. Resultant tumors had a phenotypic diversity similar to that of the original tumor and behaved in a similar manner when passaged. This effect was associated with a loss of the G1 specificity of p53-mediated cell cycle arrest. Although neither the visual interpretation nor SUVlean differentiated mature teratoma from necrosis or scar, there were statistically significant differences in the kinetic rate constants K1 and K between mature teratoma and necrosis or scar as follows: K1, 0.113 mL/min/g +/- 0.026 versus 0.036 mL/min/g +/- 0.005 (P < .05); K, 0.005 mL/min/g +/- 0.003 versus 0.0008 mL/min/g +/- 0.0001 (P < .05).FDG PET with kinetic analysis appears to be a promising method for management of disease in patients with GCT after treatment. The amine-derivatized biotinylated GM-CSF analogues retained biological activity, could specifically label cell surface receptors, and may be useful nonradioactive probes with which to study GM-CSF receptor cytochemistry and receptor modulation by flow cytometry. Until 2001 he was Deputy Vice-Principal and Director for Research Development at King's College London, where he remains a Visiting Professor of Defence Studies. List A-Z. In addition to his clinical duties in the division of Oncology, Dr. Clarke maintains a laboratory focused on two areas of research: i) the control of self-renewal of normal stem cells and their malignant counterparts; and ii) the identification and characterization of cancer stem cells. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Solid CRC tissues, either primary tissues collected from surgical specimens or xenografts established in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, were disaggregated into single-cell suspensions and analyzed by flow cytometry. BIO-IMEB - Biofilms in Industry, Medicine & Environmental Biot, Galway, Ireland, 9-14 August 2003. Han, J. S., Qian, D. L., Wicha, M. S., Clarke, M. F. Targeting cancer cell death with a bcl-x(s) adenovirus. Cytoplasmic sequestration of the mt p53 was dependent upon the C-terminal region (residues 326-355) of the protein. Therefore, functional inhibition of Bcl-2 family members is lethal to many cancer cells. RRV replication was significantly rescued in IFN types I and II, as well as STAT1 (IFN types I, II, and III) deficient mice in contrast to EW, which was only modestly sensitive to IFNs I and II. We have introduced this construct into Friend erythroleukemia (F-MEL) cells and have isolated a number of clones which contain intact and transcriptionally active human c-myb sequences. The tumorigenic subpopulation could be serially passaged: each time cells within this population generated new tumors containing additional CD44(+)CD24(-/low)Lineage(-) tumorigenic cells as well as the phenotypically diverse mixed populations of nontumorigenic cells present in the initial tumor. These results indicate that addition of combinations of hematopoietic CSFs, together with a rapid medium exchange rate, can provide culture conditions that are suitable for the expansion of the progenitor cell pool and perhaps for the increased survival of hematopoietic stem cells in culture. The plasmid vector contains simian virus 40-derived promotor, splice, and polyadenylation sequences as well as a transcription unit for a dihydrofolate reductase cDNA. 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