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PubMed1975

Erythroblastosis models. A review and new experimental data in monkeys.

The current status of erythroblastosis fetalis in man and in animals is briefly reviewed with emphasis on present knowledge of nonhuman primates as models for the disease. Our studies in crab-eating macaques indicate that presence in a mother's serum of potent antibodies reactive for red cells for her fetus will not necessarily cause erythroblastosis; in one case the maternal antibodies did not penetrate the placental barrier, and in two cases although the fetal red cells were maximally antibody-coated, they remained undamaged and the disease failed to develop.

ABO Blood-Group System↗

PubMed1975

[Pre- and postnatal treatment of severe Rh-erythroblastosis (author's transl)].

162 children with severe Rh-erythroblastosis were treated with 326 prenatal blood transfusions. 89 (55%) survived. The indication and technique for this treatment and the postnatal intensive care of the newborn are reported. Prenatal diagnosis is extended by the author's immunofluorescence technique assessing the fetal Rh factor D even as minute contamination amongst other cells, in order to privente unnecessary treatment of Rh negative children. Checking the effectiveness of prenatal blood-transfusion this technique can demonstrate differences in the counts of HbF- and D-cells. Success of treatment appears to be, in part, determined by dexamethasone just before delivery and by immediate postnatal substitution of erythrocyte concentrates and following exchange transfusion. With increasing experience the percentage of successful treatment rose. Of 40 children treated during the last 2 years with 95 prenatal transfusions, 67,5% survived. 41 fetuses had ascites already at the first prenatal transfusion. 9 of them (22%) survived. The data of the children treated, earliest in the 21st week of pregnancy, are given: Bilirubin level in amniotic fluid, number of prenatal transfusions, gestational week at delivery, hematocrit, HbF cells, number of postnatal exchange transfusions and later transfusions. Postnatal development of successfully treated children corresponds to that of other premature children without erythroblastosis.

Amniotic Fluid↗

PubMedDate not supplied

Intravenous administration of recombinant adenoviruses causes thrombocytopenia, anemia and erythroblastosis in rabbits.

BACKGROUND: Recombinant adenoviruses are highly efficient gene transfer vehicles but their administration to mammals is accompanied by a strong inflammatory response. The present study reports additional side effects observed during adenoviral gene transfer studies in rabbits. METHODS: Hematological and serological parameters, the course of viremia and the organ distribution were analyzed after in vivo administration of E1-deleted adenoviruses in rabbits. RESULTS: The systemic administration of a therapeutic dose of 5 x 10(11) infectious particles/kg (infusion time 20 min) led to an average reduction of 80-90% in the platelet count within 48 h. Full recovery took 10-14 days. Virus administration induced a strong but transient erythroblastosis (peaking 24 h after administration) which settled 48 h later. Normochromic anemia occurred over the next 10 days with hemoglobin levels dropping by about 40% to reach the lowest level 10 days after administration and taking two months for full recovery. Dose-dependent thrombocytopenia was also found in mice, but neither erythroblastosis nor anemia was observed (in equivalent doses). The hematological findings did not improve after local injection via the portal vein. Local and systemic administration led to a comparable course of viremia. Only minor differences were found in the biodistribution of viruses between local and systemic administration. Large amounts of viral DNA and transgene expression were found in the lungs, the kidneys and the ovaries, even after local administration via the portal vein. CONCLUSIONS: Local intravenous injection via the portal vein does not prevent systemic spread of viral vectors and the occurrence of vector-related side effects. The hematological changes observed in rabbits suggest the need for careful monitoring of hematological and rheological parameters in clinical trials.

Adenoviridae↗

PubMed1985

Activation of c-erbB in avian leukosis virus-induced erythroblastosis leads to the expression of a truncated EGF receptor kinase.

Chicken erythroblastosis caused by avian leukosis virus (ALV) is thought to be mediated by activation of the c-erbB/EGF receptor oncogene by a promoter-insertion mechanism. Here we study the proteins expressed by two ALV-induced leukemias and compare them with the avian EGF receptor and with the oncogene product of avian erythroblastosis virus (v-erbB) which was shown to be a truncated EGF receptor. It appears that the two leukemias express truncated EGF receptors of slightly different sizes with intrinsic tyrosine kinase activity. Hence, acute and chronic retroviruses utilize a common pathway for transformation. Moreover, the proteins expressed in the leukemias are similar to the avian EGF receptor with respect to their phosphopeptide maps, suggesting that they do not carry the C-terminal deletion characteristic of v-erbB.

Alpharetrovirus↗

PubMed1994

Reflections on the pathogenesis of diseases caused by the acute avian leukosis/sarcoma viruses with special reference to avian erythroblastosis.

The various diseases that follow experimental infection with the acute and non-acute avian oncoviruses are discussed with special reference to the pathogenesis of avian erythroblastosis. One view, based on in vitro studies, sees erythroblastosis as the product of a failure in the differentiation of virus-infected stem cells to mature erythrocytes, as a result of cell 'transformation'. The results of some in vivo studies, however, point to a resemblance of the disease to a haemolytic anaemia, where cellular death is an important component. It seems probable that the disease is the result of transformation of cells of the erythroblastic series followed by the death of many of these cells due to influences that have not yet been determined. Determination of the causes of this cellular death may prove to be as important for our understanding of the problem of leukaemia as the work that has already been accomplished in explaining the causes of cell transformation. It is also suggested that the tendency of gs amino acid sequences of the avian leukosis viruses and mouse leukaemia viruses to form fusion proteins with a variety of proto-oncogenes may be part of a wider phenomenon, and that these sequences may fuse with other proteins, altering their properties. More work is required on the possibility that there is an undiscovered immunological component in the progression of the L/S diseases.

Acute Disease↗

PubMed1984

Avian erythroblastosis virus E26: nucleotide sequence of the tripartite onc gene and of the LTR, and analysis of the cellular prototype of the viral ets sequence.

An intact 5.7-kb provirus of the avian erythroblastosis virus E26 has been molecularly cloned for comparisons with avian myeloblastosis virus (AMV) and other avian tumor viruses. E26 and AMV transform hemopoietic cells exclusively. Both cause myeloblastosis, but E26 also causes erythroblastosis. Sequence analysis of the proviral DNA showed that: The tripartite transforming gene of E26 forms a contiguous reading frame of 1046 codons, including 272 gag, 283 mybE, and 491 ets codons. No subgenomic ets-specific mRNA was detected in E26-infected cells. By contrast, the onc gene of AMV consists almost entirely of a mybA sequence expressed via subgenomic mRNA that extends over the 5' and 3' ends of mybE. mybE is only slightly diverged from the mybA homolog of AMV and even less from the cellular proto-myb sequence with no characteristic mutation that sets apart the two viruses from proto-myb. The U5 region of the long terminal repeat (LTR) of E26 and AMV are colinear and differ only in scattered point mutations. The U3 region of the E26 LTR is different from that of AMV but is colinear and closely related with that of avian carcinoma virus MH2 and also with that of Prague Rous sarcoma virus (RSV), except for an unexpected 16-nucleotide substitution of 22 RSV nucleotides. Upstream of the 3' LTR, the c region of E26 appears to be the same as that of RSV for 70 nucleotides and very similar to those of AMV and MH2 for about 20 to 30 nucleotides. Since the U3s of E26, MH2 and RSV are very closely related and neither MH2 nor RSV show a particular erythroblast tropism, it is possible that the U3 does not play a critical role in the erythroblast tropism of E26. Electrophoretic size analyses of chicken DNA digested with restriction enzymes indicate that DNA fragments totaling over 50 kb hybridize with viral ets DNA.

Alpharetrovirus↗

PubMed1983

The erbB gene of avian erythroblastosis virus is a member of the src gene family.

The erbB gene of an avian erythroblastosis virus, AEV-H, was determined to be 1812 nucleotides long and was predicted to code for a protein of 67,638 daltons. Unexpectedly, a sequence of 285 amino acids in the middle of the protein showed a significant homology (38%) with the sequence in the carboxy terminus of p60src. The nucleotide sequence of a mutant of AEV-H, td-130, which induces sarcomas but not erythroblastosis in chicken, was also analyzed. A deletion of 169 nucleotides was identified in the 3' half of the erbB gene, indicating that the gene codes for a truncated protein with the predicted molecular weight of 46,667. These findings suggest that the homologous domain of erbB protein with its N-terminal portion is sufficient for the transformation of fibroblasts and that one-third of the carboxy-terminal domain has a key role for the transformation of erythroid cells.

Alpharetrovirus↗

PubMed1983

The product of the avian erythroblastosis virus erbB locus is a glycoprotein.

Avian erythroblastosis virus (AEV) induces both erythroblastosis and fibrosarcomas in susceptible birds. A locus, v-erbB, within the viral genome has been implicated in AEV-mediated oncogenesis. We report here the detection and partial characterization of the protein product of the v-erbB oncogene in AEV-transformed cells. We obtained the antisera necessary for our analysis by expressing a portion of the molecularly cloned v-erbB locus in Escherichia coli and immunizing rabbits with the resulting bacterial erbB polypeptide. Antisera directed against the bacterial polypeptide reacted with v-erbB proteins obtained from virus-infected avian cells. By three criteria--tunicamycin inhibition, lectin binding and metabolic labeling with radioactive sugar precursors--the product of the v-erbB gene appears to be a glycoprotein.

Alpharetrovirus↗

PubMed1983

Activation of the cellular oncogene c-erbB by LTR insertion: molecular basis for induction of erythroblastosis by avian leukosis virus.

Avian leukosis virus (ALV), a slowly oncogenic retrovirus, induces in chickens a variety of neoplasms, including lymphoid leukosis and erythroblastosis. In lymphoid leukosis, a cellular oncogene, c-myc, is activated by the insertion of ALV LTR. We provide evidence that ALV utilizes a similar mechanism in erythroblastosis induction by activating a different cellular oncogene, c-erbB. We report the isolation, from leukemic erythroblast DNA, of a clone that represents the viral-cell junction fragment and carried the ALV LTR and part of the c-erbB locus. Restriction and sequence analyses reveal that the LTR is located upstream from the erbB coding region and is oriented in the same transcriptional direction; such a structure would be compatible with the promoter-insertion type of activation. Our findings provide a molecular explanation for the multipotency of slowly oncogenic retroviruses.

Animals↗

PubMed1983

Identification and characterization of the avian erythroblastosis virus erbB gene product as a membrane glycoprotein.

Avian erythroblastosis virus causes erythroid leukemia and sarcomas in chickens. The viral oncogene responsible for these diseases, erb, is divided into two regions known as erbA and erbB, and recent evidence suggests that it is the erbB gene that is responsible for the transforming activity. From rats bearing avian erythroblastosis virus-induced sarcomas, we have obtained antisera which are specific for the erb gene products. Using such antisera, we have been able to characterize the erbB gene product as a 68,000 molecular weight protein. Pulse-chase and cell-free in vitro translation experiments show that the initial product is a 62,500 dalton protein which is initially modified to a 66,000 dalton protein, and then further modified to a 68,000 dalton form. These modifications could be shown to be associated with glycosylation and phosphorylation. Cell fractionation experiments revealed that the 66,000 and 68,000 dalton proteins were located in cell membrane fractions, and immunofluorescence results showed the erbB gene product to be expressed on the cell surface.

Alpharetrovirus↗

PubMed1983

On the possible presence of beta 2-microglobulin-like protein in extracts of livers from normal chickens and chickens with erythroblastosis--II. Amino acid analysis of the protein.

1. Amino acid analyses are presented for a small molecular weight (mol. wt 11,000) protein (SMWP) obtained from the livers of normal chickens and chickens infected with erythroblastosis virus. It is resistant to acid denaturation and was isolated following acidification of liver homogenates and removal of haem and lipids. 2. Close homology exists between SMWP of fowl and human liver, and a protein of the same size obtained from chicken serum, (similar in size to human beta 2-microglobulin). 3. Human beta 2-microglobulin, virus core proteins and chicken prealbumin show a lower order relationship. 4. The amino acid residues of SMWP from healthy and erythroblastosis infected chicken livers are identical despite immunologic differences.

Alpharetrovirus↗

PubMedDate not supplied

Identification of a form of the avian erythroblastosis virus erb-B gene product at the cell surface.

Avian erythroblastosis virus (AEV) induces both erythroblastosis and fibrosarcoma in chickens. The viral oncogene responsible for these diseases, erb, is divided into two regions, erb-A and erb-B, although recent evidence suggests that it is primarily the erb-B gene product that is responsible for the transforming activity. The erb-B gene product has been reported previously to be a membrane glycoprotein of 68,000 molecular weight (MW), gp68erb -B. However, we show here that gp68erb -B is an intracellular precursor which is modified further to a 74,000 MW protein, gp74erb -B. By the criteria of resistance to digestion with endoglycosidase H, subcellular fractionation and inhibition of biosynthesis by the ionophore monensin, gp74erb -B appears to be located at the cell surface. Recently, a comparison of the erb-B sequence with that of the epidermal growth factor (EGF) receptor has shown that these two genes are highly homologous, and that erb-B appears to represent a truncated form of this growth factor. In light of these data the identification of gp74erb -B at the plasma membrane suggests that this may be the functionally important form of the erb-B gene product.

Alpharetrovirus↗

PubMed1979

Structure and specific sequences of avian erythroblastosis virus RNA: evidence for multiple classes of transforming genes among avian tumor viruses.

Two major RNA species were found in several clonal isolates of avian erythroblastosis virus (AEV) and avian erythroblastosis-associated helper virus (AEAV) complexes: one of 8.7 kilobases (kb), the other of 5.5 kb. The 5.5-kb species was identified as AEV RNA because (i) it was absent from non-transforming AEAV isolated from the same virus complex, (ii) it was present in complexes of AEV and different helper viruses, and (iii) its structure is similar to that of avian acute leukemia viruses of the MC29 group. Molecular hybridization indicated that 54% of AEV RNA is specific and 46% is related to other viruses of the avian tumor virus group, particularly to AEAV, therefore termed group-specific. The genetic structure of AEV RNA was deduced by mapping oligonucleotides representing specific and group-specific sequences and by comparing the resulting map to maps of AEAV and of other avian tumor viruses derived previously. AEV RNA contains a gag gene-related, 5' group-specific section of 1 kb, an internal AEV-specific section of 3 kb unrelated to any other viral RNA tested, and a 3' group-specific section of 1.5 kb. The 5' section of AEV RNA is closely related to analogous 5' sections of the MC29 group viruses and is homologous with a 5' RNA section that is part of the gag gene of AEAV. The 3' section is also shared with AEAV RNA and includes a variant C-oligonucleotide near the 3' end that is different from the highly conserved counterparts of all other exogenous avian tumor viruses. By analogy with Rous sarcoma virus and the acute leukemia viruses of the MC29 group, the internal specific section of AEV RNA is thought to signal a third class of onc genes in avian tumor viruses. Comparisons with AEAV and the MC29 group viruses suggest that both the 5' gag-related and the internal specific RNA sections of AEV are necessary for onc gene function.

Alpharetrovirus↗

PubMed1982

Proteins specified by avian erythroblastosis virus: coding region localization and identification of a previously undetected erb-B polypeptide.

Avian erythroblastosis virus (AEV) induces erythroblastosis and sarcomas in chickens. Two domains within the viral genome, erb-A and erb-B, have been implicated in AEV-mediated oncogenesis. By use of hybridization-arrested translations and hybridization-selections of mRNA, we have mapped on the viral genome the polypeptides specified by the erb domains. The results of hybridization-arrest with DNA representing the spliced 5' leader region of the AEV mRNA suggested that the authentic product of the erb-B domain was a 61,000 molecular weight protein, not a 41,000 molecular weight polypeptide previously identified.

Alpharetrovirus↗

PubMed1987

Reduced tyrosine kinase specific activity is associated with hypophosphorylation of pp60c-src in cells infected with avian erythroblastosis virus.

Avian erythroblastosis virus (AEV) is a replication-defective retrovirus that causes erythroblastosis and sarcomas in chickens and transforms immature erythroid cells and fibroblasts in culture. AEV encodes two oncogenes, v-erbA and v-erbB, whose products are closely related to the thyroxine receptor and the epidermal growth factor receptor, respectively. Since tyrosine protein kinases have been implicated in the process of normal growth signal transduction, we wished to study the possible consequences of the expression of these mutated, growth-regulating receptor genes on the activity of the cellular tyrosine kinase pp60c-src. A continuous cell line from AEV-infected quail embryo fibroblasts was derived that exhibited a typical transformed phenotype and expressed the viral oncogene products, p75gag-erbA and gp66-68erbB. Using an immune-complex kinase assay, we found that the specific activity of pp60c-src in AEV-transformed quail cells was decreased by a factor of 6-30 relative to that found in uninfected quail cells. A concomitant 50-80% reduction of 32Pi incorporation into the pp60c-src protein from radiolabeled, transformed cells was also observed, indicating a relationship between hypophosphorylation and diminished enzyme activity. Partial proteolytic phosphopeptide analysis revealed a decrease in phosphorylation of both serine- and tyrosine-containing peptides, suggesting an activation of specific phosphatases or inhibition of specific kinases in the AEV-transformed quail cells. Similar results were found in pp60c-src precipitated from AEV-transformed chicken and rat cells.

Alpharetrovirus↗

PubMed1984

Sequencing the erbA gene of avian erythroblastosis virus reveals a new type of oncogene.

Avian erythroblastosis virus (AEV) contains two distinct oncogenes, erbA and erbB . The erbB oncogene, which is homologous to a portion of the epidermal growth factor receptor, is related to the src family of oncogenes and efficiently transforms erythroblasts, whereas erbA potentiates the effects of erbB by blocking the differentiation of erythroblasts at an immature stage. This "potentiator" was sequenced; the amino acid sequence deduced from it was clearly different from the sequences of other known oncogene products and was related to carbonic anhydrases. These enzymes participate in the transport of carbon dioxide by erythrocytes, the precursors of which are main targets of avian erythroblastosis virus. A src-related oncogene such as erbB in synergy with an activated specific cell-derived gene such as erbA can profoundly affect early erythroid differentiation.

Alpharetrovirus↗

PubMed1980

Molecular cloning of the avian erythroblastosis virus genome and recovery of oncogenic virus by transfection of chicken cells.

Avian erythroblastosis virus (AEV) causes erythroblastosis and sarcomas in birds and transforms both erythroblasts and fibroblasts to neoplastic phenotypes in culture. The viral genetic locus required for oncogenesis by AEV is at present poorly defined; moreover, we know very little of the mechanism of tumorigenesis by the virus. To facilitate further analysis of these problems, we used molecular cloning to isolate the genome of AEV as recombinant DNA in a procaryotic vector. The identity of the isolated DNA was verified by mapping with restriction endonucleases and by tests for biological activity. The circular form of unintegrated AEV DNA was purified from synchronously infected quail cells and cloned into the EcoRI site of lambda gtWES x B. A restriction endonuclease cleavage map was established. By hybridization with complementary DNA probes representing specific parts of avian retrovirus genomes, the restriction map of the cloned AEV DNAs was correlated with a genetic map. These data show that nucleotide sequences unique to AEV comprise at least 50% of the genome and are located approximately in the middle of the AEV genome. Our data confirm and extend previous descriptions of the AEV genome obtained by other procedures. We studied in detail two recombinant clones containing AEV DNA: the topography of the viral DNA in the two clones was virtually identical, except that one clone apparently contained two copies of the terminal redundancy that occurs in linear viral DNA isolated from infected cells; the other clone probably contained only one copy of the redundant sequence. To recover infectious virus from the cloned DNA, we developed a procedure for transfection that compensated for the defectiveness of AEV in replication. We accomplished this by ligating cloned AEV DNA to the cloned DNA of a retrovirus (Rous-associated virus type 1) whose genome could complement the deficiencies of AEV. Ligation of the two viral DNAs was facilitated by using a neutral fragment of DNA as linker between otherwise noncompatible termini. Cloned AEV DNA gave rise to infectious AEV capable of transforming fibroblasts and bone marrow cells in culture and of inducing both sarcomas and erythroleukemia in chickens. We conclude that the cloned DNAs represent the authentic genome of AEV undisturbed by the cloning procedure. Molecular cloning offers a powerful approach to the identification and characterization of retrovirus genomes.

Alpharetrovirus↗

PubMed1981

Characterization of the oncogene (erb) of avian erythroblastosis virus and its cellular progenitor.

Avian erythroblastosis virus (AEV) induces primarily erythroblastosis when injected intravenously into susceptible chickens. In vitro, the hematopoietic target cells for transformation are the erythroblasts. Occasional sarcomas are also induced by intramuscular injection, and chicken or quail fibroblasts can be transformed in vitro. The transforming capacity of AEV was shown to be associated with the presence of a unique nucleotide sequence denoted erb in its genomic RNA. Using a simplified procedure, we prepared radioactive complementary DNA (cDNAaev) representative of the erb sequence at a high yield. Using a cDNAaev excess liquid hybridization technique adapted to defective retroviruses, we determined the complexity of the erb sequence to be 3,700 +/- 370 nucleotides. AEV-transformed erythroblasts, as well as fibroblasts, contained two polyadenylated viral mRNA species of 30 and 23S in similar high abundance (50 to 500 copies per cell). Both species were efficiently packaged into the virions. AEV-transformed erythroblasts contained additional high-molecular-weight mRNA species hybridizing with cDNAaev and cDNA5' but not with cDNA made to the helper leukosis virus used (cDNArep). The nature and the role, if any, of these bands remain unclear. The erb sequence had its counterpart in normal cellular DNA of all higher vertebrate species tested, including humans and fish (1 to 2 copies per haploid genome in the nonrepetitive fraction of the DNA). These cellular sequences (c-erb) were transcribed at low levels (1 to 2 RNA copies per cell) in chicken and quail fibroblasts, in which the two alleged domains of AEV-specific sequences corresponding to the 75,000- and 40,000-molecular-weight proteins seemed to be conserved phylogenetically and transcribed at similar low rates.

Alpharetrovirus↗