Ts mutants of E26 leukemia virus allow transformed myeloblasts, but not erythroblasts or fibroblasts to differentiate at the nonpermissive temperature

Beug, Hartmut; Leutz, Achim; Kahn, Patricia; Graf, Thomas

doi:10.1016/0092-8674(84)90465-3

Cited by 114 publications

(73 citation statements)

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“…Cell lines derived from these E26-transformed progenitors have proven very useful in dissecting the regulation of hematopoietic di erentiation (Kulessa et al, 1995;Rossi et al, 1996). Temperature-sensitive variants of the E26 virus have been isolated and molecularly characterized (Beug et al, 1984). Interestingly, a Gag-Myb-Ets protein with a substitution in the Myb DNA-binding domain is ts for transformation of myelomonocytic cells, whereas a mutant with a substitution in the Ets domain is ts for transformation of erythroid cells (Frykberg et al, 1988;Golay et al, 1988).…”

Section: Cells and Transformation Assays (Figure 2)mentioning

confidence: 99%

Transformation by v-Myb

1999

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Section: Cells and Transformation Assays (Figure 2)mentioning

confidence: 99%

Transformation by v-Myb

1999

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“…When inoculated into chickens, E26 induces a mixed erythroid-myeloid leukemia, although proliferation of erythroid elements predominates (10,11,18,24). Myeloid progenitors transformed by E26 grow as immature myeloblasts that do not spontaneously differentiate into mature macrophages (3,18) and are dependent on a chicken macrophage growth factor. In contrast, myeloblasts transformed by temperature-sensitive E26 mutants differentiate into resting macrophages at the nonpermissive temperature, lose their dependence on chicken macrophage growth factor, and elaborate a related growth factor (3).…”

mentioning

confidence: 99%

“…Myeloid progenitors transformed by E26 grow as immature myeloblasts that do not spontaneously differentiate into mature macrophages (3,18) and are dependent on a chicken macrophage growth factor. In contrast, myeloblasts transformed by temperature-sensitive E26 mutants differentiate into resting macrophages at the nonpermissive temperature, lose their dependence on chicken macrophage growth factor, and elaborate a related growth factor (3). These conditional E26 mutants are as competent as the wild-type virus in eliciting erythroblast transformation, suggesting that E26-specific sequences (vets) are at least partially responsible for erythroleukemia.…”

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The proto-oncogene c-ets is preferentially expressed in lymphoid cells.

Chen¹

1985

Mol. Cell. Biol.

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The transforming sequences of the avian acute leukemia virus, E26, contain two distinct oncogenes, v-mybE and v-ets, fused together. By using a probe containing v-ets sequences, polyadenylated transcripts of the c-ets proto-oncogene were detected in avian tissues; they included a major 7.0-kilobase and a minor 2.0-kilobase species. These c-ets mRNAs were detected at high levels only in lymphoid organs and in avian T and B lymphoid cell lines. A similar pattern of c-ets transcription was observed in human hematopoietic cell lines, with transcripts detected in lymphoid B and T cells but not in erythroid or myeloid cells. The E26 oncogene was inserted into an inducible expression vector, and a 90-kilodalton protein (bp9O) was produced in bacteria. Rabbit antisera raised to purified bp9O precipitated p135gamYybEets, the v-mybE-ets polyprotein expressed in E26-transformed cells, and also reacted with p50vmsbA, the transforming protein of the avian myeloblastosis virus. Antiserum to bp9O was absorbed with a bacterially synthesized v-mybA protein to remove anti-myb activity. The absorbed anti-bp9O serum retained the ability to immunoprecipitate p135gag9-YbetS from E26-transformed cells and specifically reacted with a 56-kilodalton polypeptide (p56) detected in chicken lymphoid organs and in T and B lymphocytes of both avian and human origin. The data suggest that p56 is a translational product of the c-ets proto-oncogene and imply that p56 may be involved in regulating the growth of lymphoid cells.

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“…17 To assess the relative contributions of the Ets and Myb moieties of the oncoprotein to the biology of the virus, mutants were produced that rendered either of these moieties temperature-sensitive for DNA binding. 10,11,18,19 In aggregate, these studies suggested that a functional DNA-binding domain of the Myb portion of the fusion protein is necessary to block thrombocytic (and macrophage) differentiation of E26-transformed MEP cells, 11,18 while an active Ets domain is required to block erythroid (and to a lesser extent eosinophil and myleolomonocytic) differentiation. 10,19 These observations raised the question about the target cells of E26 virus: Does the virus transform multipotent cells, or does it transform a committed progenitor, imposing a new fate?…”

Section: Introductionmentioning

confidence: 99%

E26 leukemia virus converts primitive erythroid cells into cycling multilineage progenitors

McNagny

Graf

2003

Blood

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Acute chicken leukemia retroviruses, because of their capacity to readily transform hematopoietic cells in vitro, are ideal models to study the mechanisms governing the cell-type specificity of oncoproteins. Here we analyzed the transformation specificity of 2 acute chicken leukemia retroviruses, the Myb-Etsencoding E26 virus and the ErbA/ErbBencoding avian erythroblastosis virus IntroductionThe first leukemia-inducing oncogenes discovered are those transduced by acute avian leukemia viruses. These genes encode truncated or mutated forms of cellular proteins. Acute leukemia viruses are relatively common in chickens, probably reflecting this species' unusual susceptibility to the transforming effects of a variety of oncoproteins. More than 10 different isolates of acute avian leukemia viruses have been identified, each inducing a distinct type of leukemia within a matter of weeks in vivo and transforming cultured hematopoietic cells within a few days of infection. 1 Cells transformed in vivo and in vitro closely resemble each other. 2,3 Thus, for example, hematopoietic cells transformed by the Myb-encoding avian myeloblastosis virus (AMV) resemble monoblasts while cells transformed by the ErbB and ErbA proteins of the avian erythroblastosis virus (AEV) resemble erythroblasts both in the animal and in tissue culture. [4][5][6] Crude fractionation experiments using adherence and cytotoxic antibodies as selection methods suggested that these viruses block the differentiation of their respective target cells. 7 Additional experiments have shown that transformation specificity is a property mediated by the individual viral oncogene(s) and not by the specificity of the viral envelope. 8 An exception to the rule is the avian acute leukemia E26 virus, which encodes a fused oncoprotein between the truncated cellular transcriptional activators c-Myb and c-Ets-1. This virus was originally described as an erythroleukemia virus, based on the expression in leukemic cells of the erythroid-specific histone H5 and the observation that E26-transformed hematopoietic colonies contained a small number of mature erythroid cells. 9 In addition, myelomonocytic precursors ("myeloblasts") were seen within the leukemic cell population of infected animals, and this cell type could be transformed in culture as well. 2,3 The virus therefore transforms 2 different cell types and induces a mixed "erythroid"/ myeloid leukemia. Subsequent studies have shown that the transformed "erythroid" cells actually resemble thromboblasts (the avian equivalents of megakaryocytes, which give rise to thrombocytes) and that they are, in fact, multipotent. Thus, they can be induced to differentiate into erythrocytes and thrombocytes by inactivation of the viral Ets and Myb proteins, respectively, 10,11 and into eosinophils and myeloblasts (granulocyte/macrophage precursors 12 ) by activation of the Ras and protein kinase C (PKC) pathways. 12,13 In addition, E26-transformed cells (called MEPs for Myb-Ets-transformed progenitors) express cell surface antigens cha...

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Ts mutants of E26 leukemia virus allow transformed myeloblasts, but not erythroblasts or fibroblasts to differentiate at the nonpermissive temperature

Cited by 114 publications

References 20 publications

Transformation by v-Myb

Transformation by v-Myb

The proto-oncogene c-ets is preferentially expressed in lymphoid cells.

E26 leukemia virus converts primitive erythroid cells into cycling multilineage progenitors

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