T-lymphoid, megakaryocyte, and granulocyte development are sensitive to decreases in CBFbeta dosage.
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.
Talebian
Laleh
L
Division of Hematology-Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160, USA. ivan.maillard@uphs.upenn.edu
Li
Zhe
Z
Guo
Yalin
Y
Gaudet
Justin
J
Speck
Maren E
ME
Sugiyama
Daisuke
D
Kaur
Prabhjot
P
Pear
Warren S
WS
Maillard
Ivan
I
Speck
Nancy A
NA
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
C493693:Cbfb protein, mouse; D050657:Core Binding Factor alpha Subunits; D050658:Core Binding Factor beta Subunit