E2a/Pbx1 oncogene inhibits terminal differentiation but not myeloid potential of pro-T cells.
E2a/Pbx1 is a fusion oncoprotein resulting from the t(1;19) translocation found in human pre-B acute lymphocytic leukemia and in a small number of acute T-lymphoid and myeloid leukemias. It was previously suggested that E2a/Pbx1 could cooperate with normal or oncogenic signaling pathways to immortalize myeloid and lymphoid progenitor cells. To address this question, we introduced the receptor of the macrophage-colony-stimulating factor (M-CSF-R) in pro-T cells immortalized by a conditional, estradiol-dependent, E2a/Pbx1-protein, and continuously proliferating in response to stem cell factor and interleukin-7. We asked whether M-CSF-R would be functional in an early T progenitor cell and influence the fate of E2a/Pbx1-immortalized cells. E2a-Pbx1 immortalized pro-T cells could proliferate and shifted from lymphoid to myeloid lineage after signaling through exogenously expressed M-CSF-R, irrespective of the presence of estradiol. However, terminal macrophage differentiation of the cells was obtained only when estradiol was withdrawn from cultures. This demonstrated that M-CSF-R is functional for proliferation and differentiation signaling in a T-lymphoid progenitor cell, which, in addition, unveiled myeloid potential of pro-T progenitors. Moreover, the block of differentiation induced by the E2a/Pbx1 oncogene could be modulated by hematopoietic cytokines such as M-CSF, suggesting plasticity of leukemic progenitor cells. Finally, additional experiments suggested that PU.1 and eight twenty-one transcriptional regulators might be implicated in the mechanisms of oncogenesis by E2a/Pbx1.
Bourette
R P
RP
Centre de Génétique Moléculaire et Cellulaire, UMR CNRS 5534, Villeurbanne Cedex, France. bourette@biomserv.univ-lyon1.fr
Grasset
M-F
MF
Mouchiroud
G
G
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D016236:Genes, fms / Q000235:genetics / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D015851:Interleukin-7 / Q000494:pharmacology; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D022423:Myeloid Cells / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D010587:Phagocytosis; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000494:pharmacology; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism*
D018398:Homeodomain Proteins; D015851:Interleukin-7; D015514:Oncogene Proteins, Fusion; D019089:Stem Cell Factor; C485184:enhanced green fluorescent protein; C089847:E2A-Pbx1 fusion protein; D049452:Green Fluorescent Proteins; D004958:Estradiol; D016186:Receptor, Macrophage Colony-Stimulating Factor