E26 leukemia virus converts primitive erythroid cells into cycling multilineage progenitors

Abstract

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...

Definitive erythropoiesis in chicken yolk sac

“…Another possible main source of cells for definitive erythropoiesis in the yolk sac, which has not been investigated in this work, is differentiated primitive erythrocytes. De-differentiation of chicken primitive erythroid cells into definitive type multipotential hematopoietic progenitors has been reported in culture system (McNagny and Graf, 2003). Differentiation plasticity of hematopoietic cells, with de-differentiation as one possible manifestation of the plasticity, has been increasingly realized (Dzierzak, 2002;Graf, 2002;Orkin and Zon, 2002;Prindull and Fibach, 2007).…”

Correction of a mouse model of sickle cell disease: lentiviral/antisickling β-globin gene transduction of unmobilized, purified hematopoietic stem cells

“…These cells replicate actively and are responsible for the acquisition of donor immunity in allogeneic recipients. [60][61][62] Vector insertions in these cells and in other committed lineages, which can be transformed, 63,64 may increase the risk of insertional activation of proto-oncogenes such as LMO-2. We did not observe leukemias in any of our primary or secondary transplant recipients.…”

Primitive and definitive erythropoiesis in the yolk sac: a birds eye view

“…3H). Although currently without direct evidence in the context of chicken yolk sac definitive erythropoiesis, similar hypotheses with regard to differentiation plasticity and potentials have been proposed in other systems (Dzierzak, 2002;Graf, 2002;Kingsley et al, 2006;McNagny and Graf, 2003;Orkin and Zon, 2002;Prindull and Fibach, 2007).…”