Ectopic expression of Delta4 impairs hematopoietic development and leads to lymphoproliferative disease.
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.
Millennium Pharmaceuticals, 75 Sidney Street, Cambridge, MA 02139, USA. dorsch@mpi.com
Marion
M
Dorsch
Gang
G
Zheng
David
D
Yowe
Prakash
P
Rao
Yanjun
Y
Wang
Qiong
Q
Shen
Curran
C
Murphy
Ximing
X
Xiong
Qiuju
Q
Shi
Jose-Carlos
JC
Gutierrez-Ramos
Chris
C
Fraser
Jean-Luc
JL
Villeval
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects; D001798:Blood Proteins / Q000235:genetics / Q000493:pharmacokinetics* / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002135:Calcium-Binding Proteins; D005822:Genetic Vectors; D006133:Growth Substances / Q000235:genetics / Q000493:pharmacokinetics* / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008232:Lymphoproliferative Disorders / Q000209:etiology* / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D051880:Receptors, Notch; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects; D014018:Tissue Distribution; D014161:Transduction, Genetic
D048868:Adaptor Proteins, Signal Transducing; D001798:Blood Proteins; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch