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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 Identification of the A vian Myeloblastosis Virus Genome L. M. Souza, D. G. Bergmann, and M. A. Baluda In addition to neoplasias caused in chickens by hel per viruses of the avian myeloblastosis virus (AMV) complex, acute myeloblastic leukemia is induced by a defective leukemogenic component. To identify the leukemogenic viral genome the unintegrated and integrated viral DNA intermediates were chracterized. Linear viral DNA isolated from the cytoplasm of helper virus (MAV-1 or MAV-2) infected chicken embryonic fibroblasts (CEF) has a mass of 5.3 million daltons (md) (Bergmann et al. 1980). The linear MAV-1 and MAV-2 DNAs can be distinguished from one another by cleavage with the restriction endonuclease Bind In, because MAV-1 DNA contains one more Bind In recognition site than does MAV-2. Linear viral DNA isolated from the cytoplasm of CEF infected with standard AMV (AMV -S) wh ich contains the defective leukemogenic component showed a minor molecular species of 4.9 md in addition to the major species of 5.3 md. Eco RI or Bind In digestion of the linear viral DNA from AMV S-infected CEF generates specific fragments in addition to those unique for MAV -1 or MAV-2 viral DNA (Bergmann et al. 1980). A Bind In digest of AMV -S linear viral DNA also indicates that more than 90 % of the AMV -S virus complex is MAV -llike, while the remainder represents both the leukemogenic and MAV-2-like viruses (Souza et al. 1980). The arrangement of endogenous proviral DNA in the chicken genome was determined prior to AMV infection. Infections were carried out both in vitro and in vivo using viral stocks of AMV-S, AMV-B, or AMV-C. (Souza and Baluda, to be published; Souza et al., to be published a). AMV-B contains only viruse of subgroup B, whereas AMV-S contains both subgroup A and B viruses. AMV-C originated from a clone of nonproducer myeoloblasts superinfected with tdB77 subgroup C. Peripheral blood leukemic myeloblasts induced by AMV contained two specific restrietion enzyme fragments, an Eco RI 2.2 md and a Bind In 2.6 md, in addition to the endogenous proviral pattern. These two fragments were also detected in the appropriate digest of AMV-S linear viral DNA. DNA from 16 clones of leukemic myeloblasts isolated from AMV -converted yolk sac cell cultures contained the Eco RI 2.2 md and Bind In 2.6 md fragments, regardless of the endogenous complement or the pseudotype of AMV used for conversion. In addition, 2 of the 16 leukemic myeloblast clones contained the two leukemiaspecific fragements in the absence of any detectable helper provirus (1). (Souza and Baluda, to be published; Souza et al. , to be published a). Juncture fragments between cellular and proviral sequences could be detected in the leukemic myeloblast clones, but were generally not seen in peripheral blood leukemic myeloblasts. The number of differently sized juncture fragments detected in the leukemic myeloblast clones indicated that the DNA intermediates of the AMV complex can integrate at multiple sites in host DNA (Souza et al., to be published a) Recombinant DNA clones were constructed by inserting 16-20-kilobase fragments of Eco RI partially digested leukemic myeloblast DNA into phage A. Charon 4a (Soza et al. 1980, to be published b). Clones containing proviral sequences were identified by hybridization with 125I-AMV-S RNA. Restrietion enzyme analysis of one clone, AllAl-l, showed that the proviral DNA is flanked by cellular sequences on either side, contains both the Eco 429
RI 2.2 md and Hind III 2.6 md leukemia specific fragments, and has a mass of approximately 4.9 md (Souza et al. 1980). This molecular mass is the same as that of an unintegrated linear viral DNA found in CEF infected by AMV -S but not in CEF infected by MAV-l or MAV-2. Therefore, this provirus could represent the AMV genome responsible for acute myeloblastic leukemia. Another }.. chicken hybrid clone, AlOA2-1, contained 85% of a MAV-l-like genome starting from the 5' end with respect to viral RNA. Comparison of the AMV genome from }"l1Al-l with the MAV-l-like genome from }"10A2-1 by restriction endonuc1ease mapping (Fig. 1) and 5' 3' MAV Y ! • ,. ~ Yi ,. I 6. l!I tL-lI •• • AMV Y I (md) • ! • ~ Yi 6 • ! I!I ~ lY I----i I I I I I 2 3 4 5 6 Fig. 1. Restrietion enzyme maps of the presumptive AMV and MAV-l-like genomes. Restrietion endonuclease sites are loealized for the proviral DNA of the presumptive AMV provirus in A-hybrid llAI-l and the partial MAV-l-like provirus in A-hybrid 1 OA2-1. The dashed Une in the MA V map indicates that part of the MAV-l-like genome not present in the AlOA2-1 hybrid. The loeation of the 3' terminal enzyme sites in MA V-I were determined with linear viral DNA. Enzyme sites: ('7) Hind III, (0) EeoRI, (0) Xba I, (0) Kpn I, (+) Bam HI, (.) Bgl II, and (T) Xho 1. The bar und er the AMV map represents the region of eellular substitution heteroduplex analysis indicated both genomes are homologous over 3.6 md from the 5' terminus and lack homology on the 3' side of the single Kpn I site in each genome (Souza et al. , to be published a,b). R-Ioop analyses carried out with the }..-recombinant containing the AMV genome and 35S AMV -S RNA revealed two types of R-Ioops (Souza et al., to be published b). The first type showed the RNA hybridized over the entire length of the presumptive AMV genome, while the second type showed the RNA hybridzed for approximately 5700 bases from the 5' end of the provirus, displaced by a DNA-DNA duplex for the next 900 bases, and hybridized again for the remaining 700 bases to the 3' terminus. The first type is interpreted to represent an R-Ioop of AMV RNA and the second type, and R-Ioop of MAV RNA to the AMV genome in which a contiguous 900 base substitution exists. Southern blots of Eco RI digested DNA from various strains of uninfected chickens were hybridized with either 125I-Iabeled RAV-O, MAV-2, or AMV-S RNA. In addition to the Eco RI fragments containing endogenous proviral sequences detected by the MAV -2 or RAV -0 probe, two AMV -S-specific fragments of 3.7 and 1.5 md were detected by the AMV-S probe (Souza and Baluda 1978). 32p-DNA probes prepared from the 3' region of the AMV DNA genome were hybridized to Eco RI DNA blots prepared from various strains of uninfected chickens (Souza et al. to be published b). The 32p_AMV prob es detected the same cellular sequences, Le., the same Eco RI fragments that were detected with 125I-AMV-S RNA. AMV-specific sequences could also be detected in uninfected Peking duck Eco RI DNA blots using the 3 2 P-Iabeled AMV probes. Ducks do not contain endogenous proviral DNA homologous to the known avian retroviruses. A 3 2 P-Iabeled probe made from a similar region of the MAV -l-like provirus contained only homology to endogenous proviral sequences in chicken DNAs and no homology to the Peking duck DNA (Souza et al., to be published b). These hybridization studies have demonstrated that the AMV genome contains a cellular substitution. The physical mapping studies pI ace this substitution in the region of the genome normally occuppied by the envelope gene. Thus, this cellular substitution in AMV may be responsible for its leukemogenic potential and its defectiveness. AMV differs from avian defective transforming viruses such as MC-29, AEV, and MH2 in the following: (1) AMV is only slightly smaller than its natural helper(s), (2) the substitution if contains is half the size of the substitution contained in the other defective viruses, (3) the substitution in AMV appears to only have replaced the env gene, whereas the substitutions in the other defective viruses have replaced part of gag, pol, and env, and (4) AMV does not make an unprocessed transforming protein containing part of gag (Silva and Baluda, to be published). However, the AMV genome resembles physically that of Bryan RSV, a defective avian sarcoma virus. 430
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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
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 and 394: Table 1. Oncogenic properties of re
Page 395 and 396: also Fig. 1). It followed that the
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 411 and 412: Haematology and Blood Transfusion V
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: 77:3009-3013 - Hu SSF, Moscoviei C,
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 and 464: Osteopetrosis and osteosarcomas occ
Page 465 and 466: Lymphoma cellline Table 1. T and B
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
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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
Page 497 and 498:
Page 499 and 500:
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:
Page 509 and 510:
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
Page 515 and 516:
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
Page 521 and 522:
J. HTLV Was Present in the Primary
Page 523 and 524:
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:
Page 557 and 558:
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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