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 Blood, 15 July 2008, Vol. 112, No. 2, pp. 320-329.
Prepublished online as a Blood First Edition Paper on March 13, 2008; DOI 10.1182/blood-2007-11-126300.

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HEMATOPOIESIS AND STEM CELLS

Cul4A is required for hematopoietic cell viability and its deficiency leads to apoptosis

David L. Waning1, Binghui Li1, Nan Jia1, Yahaira Naaldijk1,2, W. Scott Goebel1, Harm HogenEsch3, and Kristin T. Chun1,2

1 Herman B Wells Center for Pediatric Research, Section of Pediatric Hematology/Oncology, Department of Pediatrics, 2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis; and 3 Department of Comparative Pathobiology, Purdue University, West Lafayette, IN

In vitro studies indicate that Cul4A ubiquitin ligases target for ubiquitin-mediated proteolysis regulators of cell-cycle progression, apoptosis, development, and DNA repair. In hematopoietic cell lines, studies by our group and others showed that Cul4A ligases regulate proliferation and differentiation in maturing myeloid and erythroid cells. In vivo, Cul4A-deficient embryos die in utero. Cul4A haploinsufficient mice are viable but have fewer erythroid and primitive myeloid progenitors. Yet, little more is known about Cul4A function in vivo. To examine Cul4A function in adults, we generated mice with interferon-inducible deletion of Cul4A. Cul4A deficiency resulted in DNA damage and apoptosis of rapidly dividing cells, and mutant mice died within 3 to 10 days after induction with dramatic atrophy of the intestinal villi, bone marrow, and spleen, and with hematopoietic failure. Cul4A deletion in vivo specifically increased cellular levels of the Cul4A ligase targets Cdt1 and p27Kip1 but not other known targets. Bone marrow transplantation studies with Cul4A deletion in engrafted cells specifically isolated analysis of Cul4A function to hematopoietic cells and resulted in hematopoietic failure. These recipients died within 9 to 11 days, demonstrating that in hematopoietic cells, Cul4A is essential for survival.


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