Enforced expression of Runx2 perturbs T cell development at a stage coincident with beta-selection.
The development of T cells in the thymus is regulated by a series of stage-specific transcription factors. Deregulated expression of these factors can lead to alterations in thymocyte development with the production of aberrant cell subsets and predispose to tumor formation. The three genes of the Runx family are multilineage regulators of differentiation that have been reported to be expressed in the T cell lineage. However, their roles in thymocyte development and T cell function are largely unknown. While the Runx2/Cbfa1/AML3/Pebp2alphaa gene plays a primary role in osteogenesis and regulates a number of key bone regulatory genes, we show here that Runx2 is also expressed during the earliest phase of thymic development, in the double-negative subset. Furthermore, enforced expression of Runx2 in transgenic mice under the CD2 promoter was found to affect T cell development at a stage coincident with beta-selection, resulting in an expansion of double-negative CD4 and CD8 immature single-positive cells. Unlike wild-type controls this preselection population (CD4-CD8+heat-stable Ag+TCR-) is in a nonproliferative state, but appears to be primed for further transformation events. Overall the data suggest that Runx2 accelerates development to the CD8 immature single-positive stage, but retards subsequent differentiation to the double-positive stage. Thus, Runx2 joins a small group of transcription factors that can interfere with early T cell development, cause an expansion of a specific subset, and predispose to lymphoma.
Vaillant
François
F
Molecular Oncology Laboratory, Institute of Comparative Medicine, University of Glasgow Veterinary School, Glasgow, United Kingdom. f.vaillant@vet.gla.ac.uk
Blyth
Karen
K
Andrew
Linda
L
Neil
James C
JC
Cameron
Ewan R
ER
D000818:Animals; D018801:CD2 Antigens / Q000235:genetics / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D050659:Core Binding Factor Alpha 1 Subunit; D050676:Core Binding Factor Alpha 2 Subunit; D050657:Core Binding Factor alpha Subunits; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D019674:Genes, T-Cell Receptor beta; D016130:Immunophenotyping; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins; D011401:Promoter Regions, Genetic / Q000276:immunology; D011518:Proto-Oncogene Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology
D018801:CD2 Antigens; D050659:Core Binding Factor Alpha 1 Subunit; D050676:Core Binding Factor Alpha 2 Subunit; D050657:Core Binding Factor alpha Subunits; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; C493726:Runx1 protein, mouse; D014157:Transcription Factors