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Blood, 15 September 2002, Vol. 100, No. 6, pp. 2046-2055
HEMATOPOIESIS
Ectopic expression of Delta4 impairs hematopoietic
development and leads to lymphoproliferative disease
Marion Dorsch,
Gang Zheng,
David Yowe,
Prakash Rao,
Yanjun Wang,
Qiong Shen,
Curran Murphy,
Ximing Xiong,
Qiuju Shi,
Jose-Carlos Gutierrez-Ramos,
Chris Fraser, and
Jean-Luc Villeval
From Millennium Pharmaceuticals, Cambridge, MA; and
Department of Genetics, University of Pennsylvania School of Medicine,
Philadelphia.
Notch signaling plays a critical role in cell fate
determination in many developmental systems, including the
hematopoietic system. We and others have recently cloned a novel Notch
ligand called Delta4. In this study, we show the effect of
retrovirus-mediated ectopic expression of Delta4 in hematopoietic
cells. Lethally irradiated mice transplanted with bone marrow cells
expressing Delta4 initially suffered from leukopenia and
thrombocytopenia. Although all lineages were affected, the deficit in B
cells and platelets was the most durable and profound. A rapid
expansion of CD4+CD8+ cells occurred
shortly after transplantation. CD4+CD8+ cells
progressively invaded all tissues analyzed except the thymus, which
surprisingly was atrophic. CD4+CD8+
cells were mainly non-Delta4-transduced cells, strongly
suggesting that the disease was not cell autonomous. Around 15 weeks
after transplantation, mice died from this severe lymphoproliferative disorder, which was not transplantable in late-stage disease into secondary recipients. Mice transduced with a soluble form of
Delta4 behaved like control mice. Characterization of early
hematopoietic development revealed that Delta4 expression impaired
formation of day-12 spleen colony-forming units (CFU-Ss) and, to a
greater extent, pre-CFU-Ss. No effect was observed on myeloid
colony-forming cells (CFU-Cs), indicating that Delta4
specifically acted on the earliest hematopoietic stem cell compartment.
These results show that constitutive expression of Delta4 in
hematopoietic cells impairs the development of B cells, platelets, and
early stem cells and induces a lethal lymphoproliferative disease.
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