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Haematology and Blood nansfusion Vol. 26 <strong>Modern</strong> Trends in Human Leukemia IV Edited by Neth, Gallo, Graf, Mannweiler, Winkler © Springer-Verlag Berlin Heidelberg 1981 Genetic Approaches Toward Elucidating the Mechanisms ofType-C Virus-Induced Leukemia S. A. Aaronson, M. Barbacid, C. Y. Dunn, and E. P. Reddy A. Introduction Type-C RNA viruses may be horizontally transmitted as infectious cancer-inducing viruses or vertically transmitted from one generation to the next, often in an unexpressed form, within the host genome (for review see Aaronson and Stephenson 1976). To date the translational products of three leukemia viral genes have been identified (Baltimore 1975). The gag gene product is a polyprotein precursor that undergoes deavage to form the major nonglycosylated viral structural proteins, which for mammalian type-C viruses are p30, p15, p12, and p10. It has been possible to determine that the information within the murine viral gag gene is arranged 5'-p15-p12-p30-p10-3' (Barbacid et al. 1976). The products of the pol and env genes are, respectively, the viral reverse transcriptase and aprecursor protein containing the major envelope glycoproteins, gp70 and p15E. Evidence primarily from the avian system indicates that the type-C viral genes are ordered 5'-gag-pol-env-3' (for review see Wang et al. 1976). The lack of an in vitro transformation assay for type-C helper leukemia viruses has so far impaired efforts to elucidate the mechanisms by which these viruses cause tumor development in the animal. Thus, it is not known whether there exists a discrete viral gene that codes for a product that transforms a specific target cell population or whether the maligna nt potential of these viruses is exerted through a more indirect mechanism. The present report reviews biologic approaches currently underway within our laboratory to elucidate the mechanisms by which murine type-C viruses induce leukemia. B. Results I. Lymphoid Cell Targets for Transformation by Rauscher and Moloney MuLV Strains In an effort to study target cells for leukemia induction by murine leukemia virus (MuLV), we analyzed the kinetics of tumor formation and the histopathology of tumors induced by donal strains of two oncogenic replicationcompetent mouse type-C viruses, Rauscher and Moloney MuLV. The susceptibility of newborn NIH/Swiss mice to tumor induction by each virus was comparable. Gross enlargement of spleen and lymph nodes occurred as early as 10-11 weeks following inoculation of 5 X 10 4 XC pfu of either virus. As few as 5 X 10 2 XC pfu of each virus were capable of causing 50% mortality within 23 weeks. With Rauscher MuLV affected organs invariably induded the spleen and (less frequently) liver and peripheral or visceral lymph nodes. Thymic involvement was not detected in 50 tumor-bearing animals examined. In contrast, Moloney MuLV caused gross evidence of tumor involvement of the thymus in the majority of animals. Other lymphoid organs were also affected at high frequency. Histopathologie analysis of tumors revealed no obvious differences in the morphology of the neoplastie lymphoid cells. 11. Distribution of T and B Cell Markers Associated with MuLV -Induced Tumors As seen in Table 1, Moloney MuLV induced tumors and lymphoma celllines exhibited Thy. 1 antigen in the absence of detectable Fc or C3 receptors, indicating their T cell origin. Rauscher MuLV primary tumors and lymphoma 455
Lymphoma cellline Table 1. T and B lymphoid % Positive cells markers on cell membranes of cultured Rauscher MuLV and Thy.1 Fc C'3 Moloney MuLV -induced lymantigen receptor receptor phoma cell lines a Rauscher MuLV induced 6E
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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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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
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media. Following 24-h incubation, c
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nonleukemic eells (Greaves 1979). L
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Fig. 2. Cytocentrifuged smears of b
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Modification of amino-groups of hum
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disturb this balance in the directi
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The majority of human blood lymphoc
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of the EBV infected B cells. Howeve
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and immunoglobulins. J Immunol 120:
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" K 10 • j ~ ALL RNlL AL wtfh les
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tion akuter Leukämiezellen in "spo
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D. Results and Discussion J. Acute
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selectively responsive to different
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l1J ~ 100 ~ Q. ::) l1J Z 0 ~ z >- .
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Table 2. Growth inhibition of S49 e
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Reverse Infectious ASC/2X1Q6 transc
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munized animals to 1316 tumor cells
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Fig. 3. Expression of retroviral gp
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pg70. J Exp Med 143: 151-166 - McGr
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Table 1. Expression of tumor antige
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Virological and Molecularbiological
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Table 1. Oncogenic properties of re
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also Fig. 1). It followed that the
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whether this sequence is related to
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zed in infected cells argue that th
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a specific viral transforming prote
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detect viral RNA as the only charac
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Eisen H (1980) Myeloproliferate vir
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p,60- -34K - 1 2 3 4 Fig. 1. In vit
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.. p - • a'T ... I .t'l Fig. 4. D
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Page 413 and 414: Fig. 2. Photomicrographs of NY68 in
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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 423 and 424: Haematology and Blood Transfusion V
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
Page 449 and 450: the same animal were examined (e.g.
Page 451 and 452: I) 'IQ a \0 - CL -- Fig. 2. Restrie
Page 453 and 454: ~ ..................... ~ Cell 3' 5
Page 455 and 456: a :Sa,C! + . ~ 111 i' ( " '~ .J. b
Page 457 and 458: Table 1 Sampie Tissue TS fragment"
Page 459 and 460: a b Sac I / rep ._-_.-_ K J nl rep
Page 461 and 462: Haematology and Blood 'fiansfusion
Page 463: Osteopetrosis and osteosarcomas occ
Page 467 and 468: Table 2. In vivo growth and oneogen
Page 471 and 472: Table 1. Transforming aetivity of c
Page 473 and 474: Table 3. Transformation aetivity of
Page 475 and 476: - Shoemaker C, Goff S, Gilboa E, Pa
Page 477 and 478: indieate a shifting of target eell
Page 479 and 480: Table 2. Expression of Jl and Sourc
Page 483 and 484: ~ i ,..1---------,,':::::::::::::::
Page 485 and 486: 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
Page 491 and 492: inserts in the genome of rapidly tr
Page 493 and 494: pulations, it seemed likely that th
Page 495 and 496: contains antigens which react with
Page 499 and 500: le of reacting in sensitive radioim
Page 503 and 504: gic approach. In: Hiatt HH, Watson
Page 505 and 506: 12 Eco R [ Fig. 1. Hybridization pa
Page 509 and 510: 10 - '1~ )( -~ S:! E A U I o 1 2
Page 511 and 512: Haematology and Blood 'fransfusion
Page 513 and 514: 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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