title: T-lymphoid, megakaryocyte, and granulocyte development are sensitive to decreases in CBFbeta dosage.
abstract: The family of core-binding factors includes the DNA-binding subunits Runx1-3 and their common non-DNA-binding partner CBFbeta. We examined the collective role of core-binding factors in hematopoiesis with a hypomorphic Cbfb allelic series. Reducing CBFbeta levels by 3- or 6-fold caused abnormalities in bone development, megakaryocytes, granulocytes, and T cells. T-cell development was very sensitive to an incremental reduction of CBFbeta levels: mature thymocytes were decreased in number upon a 3-fold reduction in CBFbeta levels, and were virtually absent when CBFbeta levels were 6-fold lower. Partially penetrant consecutive differentiation blocks were found among early T-lineage progenitors within the CD4- CD8- double-negative 1 and downstream double-negative 2 thymocyte subsets. Our data define a critical CBFbeta threshold for normal T-cell development, and situate an essential role for core-binding factors during the earliest stages of T-cell development.
authors.affiliation: Division of Hematology-Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160, USA. ivan.maillard@uphs.upenn.edu
authors.forename: Laleh
authors.initials: L
authors.lastname: Talebian
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.forename: Yalin
authors.initials: Y
authors.lastname: Guo
authors.forename: Justin
authors.initials: J
authors.lastname: Gaudet
authors.forename: Maren E
authors.initials: ME
authors.lastname: Speck
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sugiyama
authors.forename: Prabhjot
authors.initials: P
authors.lastname: Kaur
authors.forename: Warren S
authors.initials: WS
authors.lastname: Pear
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Speck
mesh_terms: D000483:Alleles; D000818:Animals; D001846:Bone Development / Q000502:physiology*; D019070:Cell Lineage; D003114:Colony-Forming Units Assay; D050657:Core Binding Factor alpha Subunits / Q000502:physiology; D050658:Core Binding Factor beta Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006098:Granulocytes / Q000473:pathology*; D006410:Hematopoiesis / Q000502:physiology*; D008099:Liver / Q000196:embryology; D008533:Megakaryocytes / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011828:Radiation Chimera; D013154:Spleen / Q000196:embryology; D016176:T-Lymphocyte Subsets / Q000473:pathology*; D013950:Thymus Gland / Q000196:embryology
chemical_list: C493693:Cbfb protein, mouse; D050657:Core Binding Factor alpha Subunits; D050658:Core Binding Factor beta Subunit