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Blood, 1 January 2007, Vol. 109, No. 1, pp. 11-21.
Prepublished online as a Blood First Edition Paper on August 29, 2006; DOI 10.1182/blood-2006-05-021188.
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PLENARY PAPER
T-lymphoid, megakaryocyte, and granulocyte development are sensitive to decreases in CBFß dosage.
Laleh Talebian1,
Zhe Li1,
Yalin Guo1,
Justin Gaudet1,
Maren E. Speck1,
Daisuke Sugiyama1,
Prabhjot Kaur2,
Warren S. Pear3,
Ivan Maillard4,, and
Nancy A. Speck1,
1 Department of Biochemistry, Dartmouth Medical School, Hanover, NH;
2 Department of Pathology, Dartmouth Medical School, Hanover, NH;
3 Department of Pathology & Laboratory Medicine, Abramson Family Cancer Research Institute, Institute for Medicine & Engineering, University of Pennsylvania, Philadelphia, PA; and
4 Division of Hematology-Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA
The family of core-binding factors includes the DNA-binding subunits Runx1-3 and their common non–DNA-binding partner CBFß. We examined the collective role of core-binding factors in hematopoiesis with a hypomorphic Cbfb allelic series. Reducing CBFß 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 CBFß levels: mature thymocytes were decreased in number upon a 3-fold reduction in CBFß levels, and were virtually absent when CBFß 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 CBFß threshold for normal T-cell development, and situate an essential role for core-binding factors during the earliest stages of T-cell development.
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