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Haematology and Blood Transfusion Vol. 26 <strong>Modern</strong> Trends in Human Leukemia IV Edited by Neth, Gallo, Graf, Mannweiler, Winkler © Springer-Verlag Berlin Heidelberg 1981 Transforming Genes of Retroviruses: Definition, Specificity, and Relation to Cellular DNA * P. H. Duesberg and K. Bister A. Abstract The oncogenic properties of sarcoma, acute leukemia, and lymphatic leukemia viruses are interpreted in terms of their genetic structures. Highly oncogenic sarcoma and acute leukemia viruses are shown to contain transforming onc genes which are different from the three virion genes (gag, pol, and env) essential for replication. Biochemical and genetic approaches to define onc genes are discussed. The hallmark of retroviral onc genes is shown to be a specific RNA sequence that is unrelated to essential virion genes. On this basis five different c1asses of onc genes can be distinguished in the avian tumor virus group alone: two of these, the onc genes of Rous sarcoma virus (RSV) and avian myeloblastosis virus (AMV) , share one design. Their coding sequence is a specific RNA section which either replaces env [RSV( -), AMV] or maps adjacent to the 3' end of env (RSV). Expression of this c1ass of onc genes is mediated via subgenomic mRNAs containing sequences from the 5' end of viral RNA spliced onto the onc gene coding sequences. The onc gene product of RSV has been identified as a 60,000-dalton phosphoprotein. Three other c1asses of onc genes, namely, those of the myelocytomatosis (MC29) subgroup of viruses, avian erythroblastosis virus (AEV), and Fujinami sarcoma virus (FSV), share another design. Their coding sequences are hybrids * With minor variations this paper has been presented at three symposia during the summer of 1980: (1) Proceedings of the Third International FeHne Leukemia Meeting, St. Thomas, Virgin Islands; (2) <strong>Modern</strong> Trends in Human Leukemia IV, Wilsede, Germany; (3) 1980 International Symposium on Cancer, New York. consisting of specific as weIl as of gag or gag and pol gene-related elements. The products of these onc genes, translated from full size genomic RNA, are hybrid proteins carrying gag or gag and pol deterrninants in addition to specific sequences. They are phosphorylated and range in size from 75,000 to 200,000 daltons. Since viruses with totally different onc genes can cause the same disease (namely, RSV, FSV, AEV, and MC29 cause sarcoma and AEV, AMV, or E26 and MC29 cause erythroblastosis), it is conc1uded that multiple mechanisms involving multiple cellular targets exist for sarcomagenic and leukemic transformation of the avian cel!. Comparisons between viral onc genes of the RSV -design and in particular those of the hybrid design and onc-related chromosomal DNA sequences of the cell suggest qualitative differences. Hence viral onc genes are not simply transduced cellular genes, and cellular sequences related to viral onc genes appear not directly relevant to cancer. It follows that viral onc genes are unique and more than the sum of their parts related to cellular DNA and to replicative genes of retroviruses. We speculate that onc genes also may plan a role indirectly in cancers caused by lymphatic leukemia viruses, although these virus es are not known to contain such genes. B. Introduction Retroviruses cause sarcomas, carcinomas, acute and lymphatic leukemias, or no disease in animals (Gross 1970; Beard et al. 1973; Tooze 1973; Levy 1978; Jarrett 1978; Duesberg 1980; Essex 1980). Table 1 shows schematically the pathology of representative re- 383
Table 1. Oncogenic properties of retroviruses Viruses Tumors in animals Transformation inculture Sarcoma Carcinoma Leukemia Fibro- Blood Acute Lymphatic blast cell Sarcoma viruses RSV,RSV(-) FSV Mo-MuSV + _/+a +b _/+c + ? Ki-Ha-MuSV FeSV Acute leukemia dass I Avian MC29 subgroup: MC29, MH2, CMII, OK10 +d +d + _/+c + + AEV Abelson MuLV Acute leukemia dass II AMV,E26 + + + Lymphatic leukemia A vi an leukosis and Rous-associated viruses, tdRSV, RAV(O) _f _f +/- MuLV FeLV a Liver and kidney metastases have been reported for RSV (Gross 1970; Purehase and Burmester 1972). FeSV has been shown to cause melanocarcinomas (McCullough et al. 1972; Chen et al. 1980) b Observed among other nontumorous diseases with Harvey, Kirsten, and Moloney MuSV (see text) (Scher et al. 1975; Ostertag et al. 1980) and rarely with RSV (Gross 1970; Purehase and Burmester 1972) C Possibly due to helper virus (Gross 1970; Purehase and Burmester 1972; Graf and Beug 1978) d Not observed with Abelson virus (Rosenberg and Baltimore 1980) e Some (Beard 1973; Purehase and Burmester 1972), but not all (Moscovici 1975), stocks of AMV have caused carcinomas or sarcomas, perhaps due to other hel per virus components f Lymphatic leukemia viruses have been described to cause sarcomas and carcinomas at low frequency and after long latent periods (Gross 1970; Purehase and Burmester 1972). However, sarcoma- or carcinoma-causing variants have not been isolated troviruses of the avian, murine, and feline tumor virus groups. The avian, murine, and feline sarcoma viruses predominantly cause sarcomas and transform fibroblasts in culture. The Harvey (Ha), Kirsten (Ki), and Moloney (Mo) murine sarcoma virus es (MuSV) and rarely avian Rous sarcoma virus (RSV) also cause erythroid leukemia (Gross 1970; Scher et al. 1975; Ostertag et al. 1980; Duesberg 1980). This has not been observed with avian Fujinami virus (FSV) (Lee et al. 1980). Feline sarcoma virus (FeSV) in addition to sarcomas also causes melanocarcinomas (McCullough et al. 1972; Chen et al. 1981). The avian acute leukemia viruses of the MC29 subgroup and erythroblastosis virus (AEV) that transform fibroblasts [therefore termed "elass I" (Duesberg 1980)] and hematopoietic cells in culture have broad oncogenic spectra ineluding sarcomas and carcinomas in addition to acute leukemias in the animal (Beard et al. 1973; Graf and Beug 1978). However, the fibroblast-transforming murine Abelson leukemia virus has not been reported to cause sarcomas and carcinomas (Rosenberg and Baltimore 1980). By contrast the avian acute leukemia viruses AMV and E26 that do not transform fibroblasts in culture [therefore termed "class 11" (Duesberg 1980)] have rather specific oncogenic spectra in the animal, where they 384
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Haematology and Blood Transfusion 2
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Dr. Rolf Neth, Universitäts-Kinder
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Participants of the Meeting Aaronso
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Kurth, R, Friedrich-Miescher-Labora
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Wilsede Scholarship Holders (Grante
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Preface Gut ist eine Lehrart, wo ma
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Personal and scientific discussion
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Acknowledgement We should like to t
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Wilsede, June 21 1978 Memorial Trib
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limiting benign lymphoproliferative
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this most unlikely, however (for re
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longer subject to the same control
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Bregula U, Wiener F, Harris H (1971
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fresh lymph node biopsies from ten
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Fig. 3. Binucleate mitosis in an ob
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y Fig. 4. Schematic diagram of post
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than that among patients with Stage
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Tests of binding affinity, agglutin
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N Engl J Med 297: 963-968 - Green I
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Clinical Aspects
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"ring chromosome". "Mar" is marker,
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191 chromosomally abnormal patients
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tumors of both African and non-Afri
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Haematology and Blood Transfusion V
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Retrospective group 26/93 evolved l
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Treatment
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advantage in terms of duration of f
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leukaemia. An analysis of 168 patie
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11. Treatment Program Chemotherapy
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efractory congestive heart failure
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period (Sequence II) was gene rally
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children with a multiple drug proto
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DAYS 1 5 10 15 20 25 30 35 , I I I
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Biologically Drug Outcome fit" sens
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may counterbalance the potential be
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Ht (0--0) 50 40 30 20 10 0 Platelet
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10 7 ,-----------------------------
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11. Haematological and Biochemical
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0\ 0\ INTERFERON ... 10 3 rl E "'
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("pre-B" phenotype) has been descri
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human bone marrow cells exhibit the
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10 9.,0 MBKCC .. .,4 B prot:oool 1'
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demann W, Büehner T, Arlin Z, Gee
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-...l 00 a-tLDRENS CAt«:ER S TU>Y
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prognostic characteristics under in
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significantly higher in HR} (14.5%,
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normal or elevated immunoglobulin l
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References Andreeff M, Darzynkiewic
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R GROUP 1 ( 1970 - 1971 ) 17 PTS. R
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Table 3. Influence of initial featu
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LIJ (f) a.. < -1 LIJ Q: u. 0 >- I-
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me nt indicated that additional the
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42:2123-2134 - Chessells JM, Cornbl
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Baum et al. 1979). This study was b
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1. 0 '--'1--" 0.9 e: o .- VI VI E C
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e: o e: 1. 0 ,.--...-- 1'"'\ ......
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In conclusion, we can state that th
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Haematology and Blood Transfnsion V
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INDUCTION VCR + PRED + ASNASE (wk 3
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SCHED.INT 1 MTX • ! Adria MTX •
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~ looh---------ooooc>----o---c>----
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Consoll- Irra .tlon t) .tlon Indu
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Highrisk Standard risk Table 1. Cli
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Cumulo/ive comp/el9 remission 1.0 .
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10° 8 = 6 ö 4 Non T Cell .~ :ö
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% SURVIVAL 100 ~ ~II 0 80 60 40 - -
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a) Percentage of donor cell mitoses
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Table 5. Results of bone marrow tra
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...... w N Table 7. Clinical result
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agent had to be added and that in t
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C. Chronic Myelogenous Leukemia The
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Patients with a suitable donor rece
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No. Recurrent Leukaemia Other death
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followed by dialysis against isoton
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HS, HL- Heme >_ 40 0 HS I ;:. =====
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knowing at present. These genes may
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esistance to antifolates. In Vitro
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a DNA probe specific for the gene t
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translocation between chromosomes 9
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Table 1. Subdivision of 1827 Myelo-
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NORMAL CELL ®
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some change of the primary type, in
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F. Transformation of Mouse Bone Mar
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were carried out with 3H-MTX in the
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the lysozyme cDNA prepared from ovi
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et al. 1976). The BJAB cellline in
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dalton bands corresponding to light
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1979). The EBV-carrying cell lines
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producer lines (DAUDI and P3HR-1),
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G, Giovanella B, Westman A, Stehlin
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Dc;bt CT + i J.I9 Raji; 1. i .. 100
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c. Discussion During infectious mon
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C. Nonepisomal Viral DNA We have us
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A 260 3.0 A B 1670 70 N2 2.0 c: E .
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vivo. Nature 260:302-306 - Kirk JTO
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Fig. 1. a Polyacrylamide gelelectro
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1979). The lymphocyte subpopulation
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lysin 0 antigens are found, and mix
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Pope JH (1978) Long-term T cell-med
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Haematology and Blood Transfnsion V
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Charaeteristie Morphologie maturati
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after TPA-induction (Table 3). The
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PA (1978) Reactivity of a rabbit an
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Blood Monocyte. B lood Monocytes 1-
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and nonhistone proteins can serve a
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The findings of the evaluation of s
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Fig. 3. Tumor grawth of L 428 cells
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Cell biological and Immunological A
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consideration. Sanel (1973) obtaine
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endotoxin serum, were used. A parti
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monocytic leukemia cell line in cul
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B. Isolation, Characterization and
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don al hemopathies generally displa
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nitors. Blood Cells 6:595-607 - Min
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\I) ....I ....I IU Jl 200 r 100 90
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their haemopoietic cells' ability t
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normal normal ALL ALL ALL persons p
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64.5 { V)
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References Biermann E, Neth R, Gros
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ehambers, the growth pattern observ
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References Anderssen LC, 10kinen M,
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REH CELL UNE TO CALLb~Ö ~q~ V.M. c
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the macrophage series in which the
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Table 1. Production of factor depen
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Table 1. Characteristics of the adh
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Fig. 3. A human marrow culture at 6
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300 250 • HYPERPROLIFERATIVE PATT
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Fig. 9. Nonadherent population from
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The cobblestone areas were often no
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L (1976) Induction of colony format
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B. Materials and Methods J. Tissue
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Fig. 2. Ultrastructural appearance
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Table 1. Monoclonal antibody reacti
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al. 1979; Janossy et al. 1979) is e
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to which this is an exact replica o
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inger JL (1976) Distribution of la-
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I region antigens were found to be
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have been reported to be present on
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V. FunctionalAssays Assays for PHA
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Functional studies of UCHT1 separat
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40 ,...... (5 L.. C o u 30 .9 ~ .~
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with immunohistochemieal methods (L
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can be dissected by cloning. Utiliz
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Table 1. Origin and marker profile
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complete identity of gp 100 from no
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Page 345 and 346: media. Following 24-h incubation, c
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Page 367 and 368: D. Results and Discussion J. Acute
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Page 375 and 376: Table 2. Growth inhibition of S49 e
Page 377 and 378: Reverse Infectious ASC/2X1Q6 transc
Page 381 and 382: munized animals to 1316 tumor cells
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Page 385 and 386: Fig. 3. Expression of retroviral gp
Page 387 and 388: pg70. J Exp Med 143: 151-166 - McGr
Page 389 and 390: Table 1. Expression of tumor antige
Page 391: Virological and Molecularbiological
Page 395 and 396: also Fig. 1). It followed that the
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Page 399 and 400: zed in infected cells argue that th
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Page 403 and 404: detect viral RNA as the only charac
Page 405 and 406: Eisen H (1980) Myeloproliferate vir
Page 407 and 408: p,60- -34K - 1 2 3 4 Fig. 1. In vit
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Page 413 and 414: Fig. 2. Photomicrographs of NY68 in
Page 415 and 416: DEAE (o(lJmn 'liI GI -2 2 o e s 1
Page 417 and 418: vity was deterrnined. For endogenou
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Page 421 and 422: 85,- 66- -27 - -66 40- 27- -1'9 19-
Page 425 and 426: = 0.5 o E Q. o ILI 0.4 (J) « ILI .
Page 427 and 428: Table 1. Oncogenic potential of avi
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Page 431 and 432: Expt. No. Infecting virus Proportio
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Page 435 and 436: sequences, provided its gag portion
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Page 439 and 440: RI 2.2 md and Hind III 2.6 md leuke
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RELATIONSHIP OF ENDOGENOUS AND EXOG
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E ........ E Cl. U E :::l .... Q) (
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References Astrin S (1978) Endogeno
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the same animal were examined (e.g.
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I) 'IQ a \0 - CL -- Fig. 2. Restrie
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~ ..................... ~ Cell 3' 5
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a :Sa,C! + . ~ 111 i' ( " '~ .J. b
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Table 1 Sampie Tissue TS fragment"
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a b Sac I / rep ._-_.-_ K J nl rep
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Haematology and Blood 'fiansfusion
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Osteopetrosis and osteosarcomas occ
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Lymphoma cellline Table 1. T and B
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Table 2. In vivo growth and oneogen
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Table 1. Transforming aetivity of c
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Table 3. Transformation aetivity of
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- Shoemaker C, Goff S, Gilboa E, Pa
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indieate a shifting of target eell
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Table 2. Expression of Jl and Sourc
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~ i ,..1---------,,':::::::::::::::
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fragment of pBR322 DNA, a 3.0-kbp S
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Mak TW (1979) Proc Natl Acad Sci US
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Table 1. Transformation of 3T3 cell
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inserts in the genome of rapidly tr
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pulations, it seemed likely that th
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contains antigens which react with
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le of reacting in sensitive radioim
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gic approach. In: Hiatt HH, Watson
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12 Eco R [ Fig. 1. Hybridization pa
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10 - '1~ )( -~ S:! E A U I o 1 2
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Haematology and Blood 'fransfusion
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cultures. These cells did not conta
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indication of malignant T-cells in
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Fig. 3. Thin-section electron micro
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Table 3. Lack of detectable related
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J. HTLV Was Present in the Primary
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specific signals into nonspecific s
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Table 2. Distribution of HTLV-relat
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u 10 ~ 20 ~ :c 30 a 40 o Fig. 1. Ki
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SSV TrS-gp labeled effectively with
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60 HFF/SSV cDNA CELL RNAs: 0 HF/SSV
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Antisera a Table 1. Immunofluoresce
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Haematology and Blood 'ftansfusion
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y competition RIA yielded virtually
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SiS'V' gp70: ANTIGEN, ANTI BODY, IM
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type-C virus p30 antigen in cells f
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c. Results The fractionated whole-b
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induced antibodies as well as exper
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- Fig. la-f. Retravirus particles p
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eplication of infecting murine leuk
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immunodeficiency, multic10nal lymph
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Bovine leukemia --, proteins of 499
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Human T- cell - -, characterization
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RNA -, of tumor virus 439 Rous sarc
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Haematology andBlood Transfusion Su
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