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Blood, 15 December 2001, Vol. 98, No. 13, pp. 3793-3799
NEOPLASIA
A novel Notch ligand, Dll4, induces T-cell
leukemia/lymphoma when overexpressed in mice by retroviral-mediated
gene transfer
Xiao-Qiang Yan,
Ulla Sarmiento,
Yu Sun,
Guo Huang,
Jane Guo,
Todd Juan,
Gwyneth Van,
Mei-Ying Qi,
Sheila Scully,
Giorgio Senaldi, and
Frederick A. Fletcher
From the Department of Pathology/Pharmacology, Amgen,
Thousand Oaks, CA.
Notch receptors mediate cell-fate decisions through interaction
with specific ligands during development. The biological role of a
novel Notch ligand, Dll4, in mice was explored by
reconstituting lethally irradiated mice with bone marrow (BM) cells
transduced with Dll4 retroviral vector. White blood
cell and lymphocyte counts in Dll4-overexpressing
mice were reduced at the early stage of reconstitution but increased
significantly at approximately 10 weeks after BM transplantation. BM,
spleen, lymph nodes, and peripheral blood of
Dll4-overexpressing mice contained predominantly
CD4+CD8+ T cells and virtually lacked B
cells. The Dll4-overexpressing mice eventually developed a
lethal phenotype that was characterized by the progression of a T-cell
lymphoproliferative disease (restricted to BM and lymphoid tissues) to
transplantable monoclonal T-cell leukemia/lymphoma scattered to
multiple organs. Results suggest that the interaction of Dll4
with Notch1 may provide key signals for T-cell development.
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