E2a/Pbx1 induces the rapid proliferation of stem cell factor-dependent murine pro-T cells that cause acute T-lymphoid or myeloid leukemias in mice.
Oncoprotein E2a/Pbx1 is produced by the t(1;19) chromosomal translocation of human pre-B acute lymphoblastic leukemia. E2a/Pbx1 blocks differentiation of primary myeloid progenitors but, paradoxically, induces apoptosis in established pre-B-cell lines, and no transforming function of E2a/Pbx1 has been reported in cultured lymphoid progenitors. Here, we demonstrate that E2a/Pbx1 induces immortal proliferation of stem cell factor (SCF)-dependent pro-T thymocytes by a mechanism dependent upon both its transactivation and DNA-binding functions. E2a-Pbx1 cooperated with cytokines or activated signaling oncoproteins to induce cell division, as inactivation of conditional E2a/Pbx1 in either factor-dependent pro-T cells or pro-T cells made factor independent by expression of Bcr/Abl resulted in pro-T-cell quiescence, while reactivation of E2a/Pbx1 restored cell division. Infusion of E2a/Pbx1 pro-T cells in mice caused T lymphoblastic leukemia and, unexpectedly, acute myeloid leukemia. The acute lymphoblastic leukemia did not evidence further maturation, suggesting that E2a/Pbx1 establishes an early block in pro-T-cell development that cannot be overcome by marrow or thymic microenvironments. In an E2a/Pbx1 pro-T thymocyte clone that induced only pro-T acute lymphoblastic leukemia, coexpression of Bcr/Abl expanded its leukemic phenotype to include acute myeloid leukemia, suggesting that unique functions of cooperating signaling oncoproteins can influence the lymphoid versus myeloid character of E2a/Pbx1 leukemia and may cooperate with E2a/Pbx1 to dictate the pre-B-cell phenotype of human leukemia containing t(1;19).
Sykes
David B
DB
Department of Pathology, University of California-San Diego, La Jolla, California 92093-0612, USA.
Kamps
Mark P
MP
D000818:Animals; D002455:Cell Division / Q000502:physiology*; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000209:etiology* / Q000235:genetics; D051821:Lymphoid Enhancer-Binding Factor 1; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051880:Receptors, Notch; D012097:Repressor Proteins; D019089:Stem Cell Factor / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D008565:Membrane Proteins; D009687:Nuclear Proteins; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; D019089:Stem Cell Factor; C434946:Tle1 protein, mouse; D014157:Transcription Factors; C083400:PBX1 protein, human