Oncoprotein E2A-Pbx1 immortalizes a myeloid progenitor in primary marrow cultures without abrogating its factor-dependence.
E2A-PBX1 is a chimeric homeobox oncogene formed by the t(1;19) translocation of human pre-B cell acute lymphoblastic leukemia (ALL). In a previous study, we found that retroviral expression of E2A-Pbx1 in the marrow of reconstituted mice induced the formation of acute myeloid leukemia (AML) in vivo. Here, we report that E2A-Pbx1 can also immortalize myeloid progenitors in vitro, and that the outgrowth of immortalized myeloblasts is evident only in the presence of the myeloid lymphokine, granulocyte-macrophage colony stimulating factor (GM-CSF). When cultured in the presence of GM-CSF, responsive myeloblasts from normal marrow exhibit concurrent proliferation and differentiation, and undergo terminal differentiation into non-mitotic neutrophils and macrophages within 4 weeks. Infection of identical cultures with a retrovirus encoding E2A-Pbx1 produces a rapid outgrowth of myeloid progenitors that express high levels of E2A-Pbx1 protein. A small fraction of myeloblasts in each population exhibited limited differentiation to neutrophils, and all populations of myeloblasts retained a strict dependence on GM-CSF for both survival and proliferation. This data suggests that the function of E2A-Pbx1 in leukemias is to strongly retard differentiation without affecting growth-factor dependence.
Kamps
M P
MP
Department of Pathology, University of California, San Diego, School of Medicine, La Jolla 92093-0612.
Wright
D D
DD
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D051820:TCF Transcription Factors; C544912:TCF7L1 protein, human; C544913:Tcf7l1 protein, mouse; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; C083400:PBX1 protein, human; C089847:E2A-Pbx1 fusion protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor