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cause myeloid and erythroid leukemias (Beard et al. 1973; Moscovici 1975; Graf and Beug 1978). The viruses listed thus far have in common that they transform quiekly, within 1-2 weeks, and that transformation is an inevitable consequence of infection in susceptible animals. This implies that transforming onc genes are integral parts of the genomes of these viruses. This appears not to be true for the majority of naturally occurring retroviruses, the lymphatie leukemia viruses. These are rather ubiquitous, nondefective virus es that often cause viremias but rarely and in partieular not simultaneously cause leukemias (Gross 1970; Tooze 1973), as for example in chiekens (Rubin et al. 1962; Weyl and Dougherty 1977), mice (Gardner et al. 1976; Levy 1978 ; Cloyd et al. 1980), or cats (Jarrett 1978; Essex 1980). The transformation-defective (td), srcdeletion mutants of RSV have the same biologie (Biggs et al. 1972) and genetie properti es (Wang et al. 1976) as the lymphatie leukemia viruses (Fig. 1). The RNA genome of these viruses contains a 3'terminal c-region and all three essential virion genes in the following 5' to 3' order: gag (for internal virion proteins or group-specific antigens), pol (for RNA dependent DNA polymerase ), and env (for envelope glycoprotein). The c-region has regulatory functions in the reverse transcription of viral RNA and in the transcription of proviral DNA (Fig. 1) (Wang et al. 1975; Wang 1978; Tsiehlis and Coffin 1980). The endogenous, nondefective (containing all three virion genes) retroviruses of chicken, such as RAV(O) (Tooze 1973), and of mice, such as xenotropic viruses (Levy 1978; Cloyd et al. 1980), are inherited according to Mendelian geneties. These viruses probably never cause a disease directly and appear to differ from the more pathogenic lymphatic leukemia virus es in minor genetie elements, including the c-region that influences virus expression (Tsiehlis and Coffin 1980; Lung et al. 1980; Cloyd et al. 1980). Since transformation is not or is only rarely a consequence of replication by any of these viruses and only occurs after considerable latent periods, these virus es may not contain authentie onc genes. In the following we will describe the definition of onc genes of the rapidly transforming sarcoma and acute leukemia viruses. On this basis we will then ask whether the oncogenic specificity of some and the lack of specificity by other viruses is due to distinct onc genes or whether one onc gene can cause multiple forms of cancer. In addition, we review the quest ion of the relationship between viral onc genes and cellular DNA. Finally, the quest ion is addressed of how lymphatic leukemia viruses, whieh lack known onc genes, may cause cancer. The focus will be on avian tumor viruses, because their genetic structures are bett er defined than those of other viruses. This review extends two previous ones published recently (Duesberg, 1980; Bister and Duesberg 1980). C. Definition of src, the onc Gene of RSV The only onc gene of retroviruses for whieh nearly complete genetic and biochemieal definitions are available is the src gene of RSV. In 1970 the src gene was formally distinguished from the three essential virion genes of nondefective RSV by the isolation of a mutant that was temperature-sensitive only in transformation but not in virus replication (Martin 1970) and by the isolation of nonconditional src-deletion mutants (Duesberg and Vogt 1970 ; Martin and Duesberg 1972). These transformation-defective src deletion mutants retain all virion genes and are physically and serologically like wild type RSV (Fig. 1) (Wang et al. 1975; Wang 1978). However the RNA of the wild type measures 10 kb (kilobases) whereas that of the tdRSV measures only 8.5 kb (Fig. 1) (Duesberg and Vogt 1970, 1973; Lai et al. 1973; Beemon et al. 1974; Wang 1978). On the basis of this difference src gene-specific RNA sequences were first defined by subtracting from the 10-kb RNA of RSV with the genetic structure 5' gag-pol-env-src-c 3' the 8.5-kb RNA of the isogenic src deletion mutant tdRSV with the genetie structure 5' gag-pol-env-c 3' (Fig. 1) (Lai et al. 1973). The 1.5 kb that set apart the wild type RSV from the src deletion mutant were shown to be a contiguous sequence that mapped ne ar the 3' end of viral RNA (Wang et al. 1975). The src gene was independently defined by recombination analysis in whieh a src-deletion mutant with variant virion genes (5' gag"-pol" env"-c 3') was allowed to recombine with a nondefective RSV. All sarcomagenie recombinants with variant virion genes had the genetic structure 5' gag"-pol"-env"-src-c 3') and hence had inherited the src gene (Beemon et al. 1974; Wang et al. 1976; Wang 1978) (see 385
also Fig. 1). It followed that the 1.5-kb sequence of RSV -specific RNA was necessary for transformation. 5' o I 234 I I I 5 6 I I 7 8 9 I I I r-----,-------,-------r---. leukemia virus I gag J pol Iym phot i C env or td RSV ~.----------~-------------~--------~~ 1----- pr 180 -------I I I--pr64--f I--pr76~ I c I RSV gag pol env [:%~:a 1-----pr 180 -----; I ~pr64-l I--pr 76----4 RSV(-) gag pol [7ii] c I I pr 180 ------+ I 1-60kd--j I-- pr 76 ----I AMV gag pol [fTIa c I FSV I pr 180 ------t 1 1-35kd?-l I-- pr 76 ----4 ILlgOg~~· c I r--140kd-~ MC29 I~og~:f:'~~~ ~env I 1---II0kd----l c I MH2 ~90~:~~~:~ .1env I c I A major step towards proving that the 1.5-kb src-specific RNA sequence was also (almost) sufficient for transformation was ta- MC29 1---I00kd ---l subgroup CMn ~env c I~Og~~p~/1 ~90kd~ 1-60kd4 OKIO gag I .1pol ~i~~:~ .1env cl 3' 10 I kiloboses c I Replicatlon - defectlve vlruses AEV I I--pr76--l 200kd I.1g0g~~ e~v I c I t--75kd-l 1-40kd?-! Fig. 1. Genetic structures of viruses of the avian tumor virus group. White boxes indicate map locations and complexities in kilobases of complete or partial (L\) complements of the three essential virion genes gag, pol and env and of the noncoding c region at the 3' end of viral RNAs. Hatched boxes indicate location and complexities of specific sequence elements which are unrelated to essential virion genes and which define five distinct RNA subgroups within the avian tumor virus group. These specific sequences represent all (src, amv) or part (fsv, mev, aev) of the co ding sequences of the five different onc genes associated with avian tumor viruses. Undulated lines indicate that translation crosses and half-undulated lines that translation may cross borders between RNA sequence elements of different genetic origin. Lines under the boxes symbolize the complexities in kilodaltons of the protein products encoded by the respective RNA sequences 386
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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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Table 1. Reaction of single anti se
Page 343 and 344: Haematology and Blood Transfusion V
Page 345 and 346: media. Following 24-h incubation, c
Page 347 and 348: nonleukemic eells (Greaves 1979). L
Page 351 and 352: Fig. 2. Cytocentrifuged smears of b
Page 353 and 354: Modification of amino-groups of hum
Page 355 and 356: disturb this balance in the directi
Page 357 and 358: The majority of human blood lymphoc
Page 359 and 360: of the EBV infected B cells. Howeve
Page 361 and 362: and immunoglobulins. J Immunol 120:
Page 363 and 364: " K 10 • j ~ ALL RNlL AL wtfh les
Page 365 and 366: tion akuter Leukämiezellen in "spo
Page 367 and 368: D. Results and Discussion J. Acute
Page 369 and 370: selectively responsive to different
Page 373 and 374: l1J ~ 100 ~ Q. ::) l1J Z 0 ~ z >- .
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
Page 383 and 384: Haematology and Blood Transfnsion V
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 and 392: Virological and Molecularbiological
Page 393: Table 1. Oncogenic properties of re
Page 397 and 398: whether this sequence is related to
Page 399 and 400: zed in infected cells argue that th
Page 401 and 402: a specific viral transforming prote
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
Page 409 and 410: .. p - • a'T ... I .t'l Fig. 4. D
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
Page 419 and 420: pr 180 - - - P 12/15 - A B c D E F
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
Page 429 and 430: 100 III GI c: o "8 80 > w
Page 431 and 432: Expt. No. Infecting virus Proportio
Page 433 and 434: Haematology and Blood 'fransfusion
Page 435 and 436: sequences, provided its gag portion
Page 437 and 438: 77:3009-3013 - Hu SSF, Moscoviei C,
Page 439 and 440: RI 2.2 md and Hind III 2.6 md leuke
Page 443 and 444: RELATIONSHIP OF ENDOGENOUS AND EXOG
Page 445 and 446:
E ........ E Cl. U E :::l .... Q) (
Page 447 and 448:
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
Page 469 and 470:
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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
Page 481 and 482:
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~ i ,..1---------,,':::::::::::::::
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fragment of pBR322 DNA, a 3.0-kbp S
Page 487 and 488:
Mak TW (1979) Proc Natl Acad Sci US
Page 489 and 490:
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
Page 507 and 508:
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10 - '1~ )( -~ S:! E A U I o 1 2
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Haematology and Blood 'fransfusion
Page 513 and 514:
cultures. These cells did not conta
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indication of malignant T-cells in
Page 517 and 518:
Fig. 3. Thin-section electron micro
Page 519 and 520:
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
Page 525 and 526:
Table 2. Distribution of HTLV-relat
Page 527 and 528:
u 10 ~ 20 ~ :c 30 a 40 o Fig. 1. Ki
Page 529 and 530:
Page 531 and 532:
SSV TrS-gp labeled effectively with
Page 533 and 534:
Page 535 and 536:
60 HFF/SSV cDNA CELL RNAs: 0 HF/SSV
Page 537 and 538:
Antisera a Table 1. Immunofluoresce
Page 539 and 540:
Haematology and Blood 'ftansfusion
Page 541 and 542:
y competition RIA yielded virtually
Page 543 and 544:
SiS'V' gp70: ANTIGEN, ANTI BODY, IM
Page 545 and 546:
type-C virus p30 antigen in cells f
Page 547 and 548:
c. Results The fractionated whole-b
Page 549 and 550:
induced antibodies as well as exper
Page 551 and 552:
- Fig. la-f. Retravirus particles p
Page 553 and 554:
eplication of infecting murine leuk
Page 555 and 556:
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immunodeficiency, multic10nal lymph
Page 559 and 560:
Bovine leukemia --, proteins of 499
Page 561 and 562:
Human T- cell - -, characterization
Page 563 and 564:
RNA -, of tumor virus 439 Rous sarc
Page 565 and 566:
Haematology andBlood Transfusion Su
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