Submitted May 3, 2006
Accepted August 9, 2006
T lymphoid, megakaryocyte, and granulocyte development
are sensitive to decreases in CBF
dosage
Laleh Talebian, Zhe Li, Yalin Guo, Justin Gaudet, Maren E Speck, Daisuke Sugiyama, Prabhjot Kaur, Warren S. Pear, Ivan Maillard, and Nancy A. Speck*
Department of Biochemistry, Dartmouth Medical School, Hanover, NH, USA
Department of Pathology, Dartmouth Medical School, Hanover, NH, USA
Institute for Medicine & Engineering, University of Pennsylvania, Philadelphia, PA, USA
Division of Hematology-Oncology, University of Pennsylvania School of Medicine, Philadelphia,PA, USA
* Corresponding author; email: nancy.speck{at}dartmouth.edu.
The family of core binding factors includes the DNA-
binding subunits Runx1-3 and their common non-DNA
binding partner CBF
. We examined the collective
role of core binding factors in hematopoiesis with a
hypomorphic Cbfb allelic series. Reducing CBF
levels by three- or six-fold caused abnormalities in
bone, megakaryocytes, granulocytes and T cells. T cell
development was very sensitive to an incremental
reduction of CBF levels: mature thymocytes were
decreased in number upon a three-fold reduction in CBF levels, and were virtually absent when CBF
levels were six-fold lower. Partially penetrant
consecutive differentiation blocks were found amongst
early T lineage progenitors within the CD4- CD8- double
negative 1 and downstream double negative 2 thymocyte
subsets. Our data define a critical CBF threshold
for normal T cell development, and situate an essential
role for core binding factors during the earliest stages
of T cell development.
