title: Deletion of genes encoding PU.1 and Spi-B in B cells impairs differentiation and induces pre-B cell acute lymphoblastic leukemia.
abstract: The E26 transformation-specific (Ets) transcription factor PU.1 is required to generate lymphoid progenitor cells from hematopoietic stem cells, but it is not required to generate B cells from committed B-cell lineage progenitors. We hypothesized that PU.1 function in B-cell differentiation is complemented by the related Ets transcription factor Spi-B. To test this hypothesis, mice were generated lacking both PU.1 and Spi-B in the B-cell lineage. Unlike mice lacking PU.1 or Spi-B, mice deficient in both PU.1 and Spi-B in the B-cell lineage had reduced frequencies of B cells as well as impaired B-cell differentiation. Strikingly, all PU.1 and Spi-B-deficient mice developed pre-B cell acute lymphoblastic leukemia before 30 weeks of age. Pre-B cells accumulated in the thymus resulting in massive thymic enlargement and dyspnea. These findings demonstrate that PU.1 and Spi-B are essential transcriptional regulators of B-cell differentiation as well as novel tumor suppressors in the B-cell lineage.
authors.affiliation: Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Sokalski
authors.forename: Stephen K H
authors.initials: SK
authors.lastname: Li
authors.forename: Ian
authors.initials: I
authors.lastname: Welch
authors.forename: Heather-Anne T
authors.initials: HA
authors.lastname: Cadieux-Pitre
authors.forename: Marek R
authors.initials: MR
authors.lastname: Gruca
authors.forename: Rodney P
authors.initials: RP
authors.lastname: DeKoter
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000502:physiology; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002454:Cell Differentiation; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets / Q000502:physiology*; D017384:Sequence Deletion; D015534:Trans-Activators / Q000502:physiology*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D018941:Antigens, CD19; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C514177:Spi-B protein, mouse