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NEOPLASIA
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.
(Blood. 2001;98:3793-3799) Notch activity affects the implementation of
differentiation, proliferation, and apoptotic programs in vertebrate
cell populations.1 Recent studies have suggested that
Notch signaling plays an important role in the development of a variety
of diseases. The association of Notch1 with human disease was first
documented in a subset of T-cell acute lymphoblastic leukemia/lymphoma
(T-ALL).2 The chromosomal translocation t(7;9)
(q34;q34.3) joins the 3' portion of Notch1, initially named
translocation-associated Notch homology-1 (TAN-1), to the J Recently, Shutter et al9 reported the cloning of a novel
Notch ligand, Delta-like 4 (Dll4). Dll4 is
expressed mainly in vascular endothelial cells, but it is also found in
nonvascular cell types. Dll4 activates Notch1- and
Notch4-signaling pathways, as demonstrated by coexpression of mNotch1
or mNotch4 with Dll4, resulting in induced ESR-1 and ESR-7
messenger RNA expression in the neural ectoderm of
Xenopus embryos.9
In this study, we explored the biological role of Dll4 in
vivo by overexpressing Dll4 in the hematopoietic
system of adult mice using retroviral-mediated gene transfer. We
generated recombinant retrovirus carrying the full-length Dll4
complementary DNA (cDNA). Donor BM cells transduced with
Dll4 retrovirus were transplanted into lethally irradiated
recipient mice. We characterized the in vivo effects resulting from
overexpressing Dll4 in the reconstituted animals.
Dll4 retrovirus
BM transduction and transplantation
Analysis of DNA, RNA
Fluorescence-activated cell sorter analysis Cells collected from thymus, lymph nodes, spleen, peripheral blood (PB), and BM were stained by direct immunofluorescence double staining with anti-CD3 and anti-CD45R (B220), anti-CD4 and anti-CD8, and anti-TRC and anti-T-cell receptor (TCR)  pairs of
monoclonal antibodies (Pharmingen, San Diego, CA). Cells were analyzed
by flow cytometry by means of a FACScan analyzer (Becton Dickinson,
Lincoln, NY). Percentages of positively stained lymphocytes were
defined by gating cells with reference to their forward and side
light-scattering properties and by comparing their fluorescence intensity with that of cells stained with an isotype control pair of
monoclonal antibodies.
Histological analysis Standard histopatholgical analysis was performed.12 Briefly, tissues were fixed by immersion in 10% zinc-buffered formalin, embedded in paraffin, and sectioned and stained with hematoxylin and eosin (H&E). For immunohistochemistry staining, tissue sections were deparaffinized and stained with rabbit polyclonal antibody (Dako, Carpinteria, CA) to mouse CD3 and rat monoclonal antibody (Pharmingen) to mouse CD45R/B220. A Vectastain ABC kit (Vector Laboratories, Burlingame, CA) was used with 3,3'-diaminobenzidine tetrahydrochloride (Dako) as chromogen, and Mayer hematoxylin according to the manufacturer's instructions.RNAse protection assay and in situ hybridization RNAse protection assay (RPA) was performed by means of the RPA II kit (Ambion, Austin, TX). Radiolabeled antisense RNA probes for bcl-2 (nucleotides 1846-2034 from Gb:M16506) bcl-XL (nucleotides 527-735 from L35049), and a 103-bp murine cyclophilin probe (Ambion) were hybridized to total RNA from each sample. Quantitation was performed with a phosphor imager and ImageQuant software (Molecular Dynamics, Sunnyvale, CA). In situ hybridization for Dll4 and neo was performed with a 33P-labeled antisense probe on paraffin sections as previously described.9 A P32-labeled sense strand was used as negative control for the in situ hybridization.
Dll4-overexpressing mice Dll4-overexpressing mice and control mice were generated by transplantation into lethally irradiated animals of BM cells that had been transduced with recombinant retrovirus containing either Dll4 (Figure 1A) or the parental vector, MSCV. In these studies, 6 independent experiments, resulting in 80 Dll4-overexpressing animals and 60 control animals, were performed. Lethally irradiated recipient mice received a transplant of 7.2 ± 2.3 × 106 G418-selected cells. Northern analysis of total RNA prepared from BM and spleen cells of Dll4-overexpressing mice showed high levels of Dll4 expression (Figure 1B).Results of PB analysis in transplant recipients are shown in Figure
2. In the early phase of reconstitution,
WBC (Figure 2A) and lymphocyte (Figure 2B) counts in the
Dll4-overexpressing mice were low compared with those of
control mice. WBC and lymphocyte counts in some
Dll4-overexpressing mice started to increase at approximately 8 weeks after BMT, ranging from .026 to
.28 × 109/L (26 to
280 × 103/µL) and .022 to
.26 × 109/L (22 to 260 × 103/µL),
respectively. All affected animals died within 2 weeks after the
lymphocyte count elevation and exhibited decreased red blood cell
counts and hematocrit (data not shown). At 16 weeks after BMT,
60% of the Dll4-overexpressing mice were dead.
The effects of Dll4 overexpression on hematopoietic precursors were evaluated in a colony assay. At 4 weeks after BMT, a 3-fold decrease of marrow-nucleated cell number was seen in Dll4-overexpressing mice. The number of erythroid CFUs (CFU-Es), burst-forming units (BFU-Es), megakaryocyte colony-forming cells (CFC-Megs), granulocyte-macrophage CFCs (CFC-GMs), and multilineage CFCs per femur in Dll4-overexpressing mice decreased 7.2-, 4.1-, 5.7-, 4.6-, and 10.8-fold, respectively, compared with control mice (Figure 2C). At the same time, a 4-fold increase of splenic cellularity was observed in the Dll4-overexpressing mice. The number of CFU-Es, BFU-Es, CFC-Megs, CFC-GMs, and multilineage CFCs per spleen increased 7.4-, 2.7-, 9.1-, 4.4-, and 4.4-fold, respectively (Figure 2D). At 8.5 weeks after BMT, the BM of Dll4-overexpressing animals had a 35% increase in cellularity and contained a large number of infiltrating T cells. Total CFCs were decreased 35-fold in Dll4-overexpressing BM compared with controls, whereas splenic CFCs were increased 200-fold compared with controls. No significant difference was seen between the control and Dll4-overexpressing mice in the ratios of erythroid, megakaryocytic, granulocyte/macrophage, and multilineage CFCs. These data demonstrate increased extramedullary hematopoiesis in Dll4-overexpressing mice but no effect on the development of myeloid lineages. Effects of Dll4 overexpression on lymphocyte development At 4 weeks after BMT, the lymph nodes, spleen, PB, and BM of Dll4-overexpressing mice showed few CD3 B220+ cells, but a considerable number of
CD4+CD8+ cells (Figure
3). Many of these
CD4+CD8+ cells appeared to be CD3
(data not shown). Most of the CD4+CD8+ cells
were TCR (data not shown). The absolute number of
B cells in the spleens (4.48 ± 2.07 × 106;
n = 5) and BM (0.13 ± 0.06 × 106; n = 5) of
the Dll4-overexpressing mice was lower
(P < .01) than in the spleens
(112.5 ± 7.7 × 106) and BM
(1.59 ± 0.13 × 106) of control mice, reflecting the
decrease in B-cell percentages and suggesting a block in B-cell
development. At 16 weeks after BMT, all surviving
Dll4-overexpressing mice had a virtual lack of
CD3B220+ cells in the lymph nodes, spleen,
PB, and BM (data not shown). The Dll4-overexpressing mice
showed a marked increase in number of CD3+ and
TCR+ cells, accompanied by variable changes in CD4
and/or CD8 expression. Of 6 Dll4-overexpressing mice
analyzed, 4 mice showed an increase in CD4+CD8+
cells, and 1 of these 4 had an additional increase in
CD4CD8+ cells. The other 2 mice showed an
increase in CD4CD8 cells. These results
demonstrate that overexpression of Dll4 blocks the
development of B cells and alters the development of T cells at
various stages.
Dll4 overexpression induced transplantable T-cell leukemia/lymphoma Histological analysis was performed on 15 control and 16 Dll4-overexpressing BDF1 mice from 5 independent experiments at 4 to 19 weeks after BMT. The Dll4-overexpressing mice developed a phenotype characterized by progression of T-cell lymphoproliferative disease (restricted to BM and lymphoid tissues) to monoclonal T-cell leukemia/lymphoma involving multiple organs.In the early lymphoproliferative disease (by 4 weeks after BMT), a 2- to 3-fold increase in the spleen weight was evident with no apparent
changes in the thymus or liver weights compared with the vector control
group. In more advanced disease (by 12 weeks after BMT), marked to
massive enlargement of the spleen (with 2- to 34-fold increase in
weight), liver (1.4- to 5.8-fold weight increase), and lymph nodes was
evident with loss of body weight in the Dll4-transduced
mice. The early lymphoproliferative disease was characterized by
multifocal (at 4 weeks) to diffuse (at 12 weeks; Figure
4B) infiltration of the BM by sheets of
densely packed, monomorphic CD3+ T cells (Figure 4B,
inset). The cytomorphology of these cells differed among individual
animals: the infiltrates were predominantly medium lymphoblasts in some
mice and medium to large polymorphous lymphocytes with a prominent
"starry sky" macrophage pattern in other mice. The thymus appeared
normal (2 of 5 mice) or infiltrated (3 of 5 mice) at 4 weeks after BMT,
but had lobular to diffuse thymic atrophy (involution) by 12 weeks
after BMT. In the early disease, the mesenteric lymph nodes were
enlarged with conspicuous expansion of the medullary cords by
CD3+ T cells accompanied by B-cell (follicular) hypoplasia
and paracortical hypocellularity. In later stages, the lymph nodes and
perinodal tissues were diffusely infiltrated by neoplastic T
cells (Figure 4D). In the small intestine, the Peyer patches
(gut-associated lymphoid tissue) were also enlarged and were composed
of monomorphic T cells, which infiltrated the overlying intestinal
mucosa and villi. The spleen had a prominent periarteriolar infiltrate
of monomorphic CD3+ T cells extending into the red pulp,
which also had extramedullary hematopoiesis.
In more advanced disease, Dll4-overexpressing mice had disseminated T-cell leukemia/lymphoma with enlargement, architectural effacement, and multifocal to diffuse infiltration of lymphoid and nonlymphoid organs and tissues, including the BM, lymph nodes (Figure 4D), spleen, liver (Figure 4F), lung, heart, thymus, urogenital tract, and PB (frank leukemia). In some mice, the BM cavity had focal to diffuse myelofibrosis with new bone formation (fibro-osseous lesion) and scattered remnants of hematopoietic cells mixed with neoplastic lymphocytes. Similar neoplastic lymphoid infiltrates were also found surrounding vessels or in the interstitial tissues in the heart, kidneys, stomach, pancreas, lung, brain (leptomeninges and choroid plexus), thyroid, ovary, oviduct, uterus, cervix, and urinary bladder. The T-cell leukemia/lymphoma in the Dll4-overexpressing mice were morphologically heterogenous. Consistent with fluorescence-activated cell sorting (FACS) analysis results, these data suggest that overexpression of Dll4 results in the proliferation and transformation of T cells at different developmental stages. To confirm the development of T-cell transformation in the
Dll4-overexpressing mice, spleen cells were harvested from 5 Dll4-overexpressing mice 17 weeks after BMT and injected
into 50 secondary nonirradiated BDF1 mice. Each donor
spleen was injected into 10 recipients, and each recipient received
2 × 107 spleen cells. Four of 5 groups (Figure
5B,D-F) developed acute lymphoma that was
characterized by elevated WBC, lymphocytes, and lymphoblasts in PB
(Figure 5, inset). All animals in groups (panels) B, D, E, and F died
between 4 to 6 weeks after BMT. Seven of 10 mice in group C were alive
at 9 weeks after BMT with elevated WBC and lymphocyte counts. When
spleen cells from group C were further transplanted into tertiary
normal BDF1 mice, elevation of WBC, lymphocytes, and
lymphoblasts was observed at 3 to 4 weeks after transplantation (data
not shown). Transplantation of spleen cells from the control group did
not affect lymphocyte number in secondary recipients (Figure 5A).
Histological analysis of the viable mice confirmed the development of
aggressive lymphoma in multiple organs (data not shown).
We also analyzed the lymphoma clonality in donor and recipient
mice by proviral junction analysis. DNA was extracted from BM and
spleens of donor mice and from secondary and tertiary transplant recipients. DNA samples were digested with SpeI, which has a
single recognition site within the provirus (Figure 1A), and hybridized with 32P-labeled neo fragment.
Dll4-overexpressing animals that were used as donors at 17 weeks after BMT had 1 or 2 virally marked clones (Figure
6). The expansion of single clones
(marked by arrows in panel A) was seen in the spleens of secondary
(groups F-2nd, D-2nd, C-2nd) and tertiary (group C-3rd) transplant
recipients (panel B). The same results were also seen in the BM of the
secondary and tertiary transplant recipients (data not shown).
Expression of Dll4 in the thymus Dll4 is expressed predominantly in vascular endothelial cells.9 Our data suggest a role for Dll4 in T-cell development. We therefore examined whether Dll4 is expressed in the thymus of normal mice by in situ hybridization. Dll4 is expressed in normal cortical thymocytes, especially in the subcapsular region (Figure 7), where immature double-negative and double-positive thymocytes are located and where Notch1 and Notch3 are also highly expressed.14 Expression of Dll4 was also shown in the vascular endothelial cells as previously reported.9
Expression of Dll4 in lymphoma cells To address whether all lymphoma cells express Dll4, we examined Dll4-overexpressing animals at 10.5 weeks after BMT. These animals were diagnosed with lymphoma by histopathological analysis. We performed imunohistochemistry staining using anti-CD3 antibodies and in situ hybridization using antisense neo and Dll4 genes on adjacent liver and spleen sections. Massive infiltration with lymphoblastlike (lymphoma) cells were seen in both spleen and liver. Most of the lymphoblastlike cells were CD3+ (Figure 8A, mouse 21). Approximately one third of the lymphoma cells expressed high levels of neo RNA message (Figure 8B). Approximately one tenth of the lymphoma cells expressed high levels of Dll4 (Figure 8C). Most of the CD3+ cells expressed undetectable levels of neo or Dll4 RNA. Mouse 21 was repopulated with one major (Figure 8D, labeled a) and one minor clone (Figure 8D, labeled b). Similar results were obtained with other analyzed animals.
Dll4 may play a role in the control of endothelial biology because it is highly expressed in embryonic and adult vascular endothelium.9 In our studies, we established a mouse model to explore the biological role of Dll4 in vivo by overexpressing the Dll4 cDNA in the hematopoietic system using retroviral-mediated gene transfer. We evaluated systematic effects in the Dll4-overexpressing mice but did not observe any significant endothelium-related phenotype. Instead, the phenotype in our animals closely mimics that reported by Pear et al3 that is due to persistent activation of Notch1. We suggest that Dll4 is a natural ligand for Notch1 and plays an important role in T-cell development. This notion agrees with reports describing the effects of activation of Notch1 in a number of in vivo models. Constitutively activated Notch1 (TAN-1) was demonstrated to be responsible for the development of a subset of T-ALL in humans.2 Subsequently, it was shown that mice that received BM cells that were transduced with retrovirus encoding Notch1-IC developed clonal T-cell leukemia.3 When these animals were examined at an early stage of reconstitution, mice that overexpressed the Notch-IC produced immature, double-positive T cells in the BM and a blockage in early B-cell development, but myelopoiesis was not affected.15 Notch-IC-overexpressing animals eventually developed T-cell leukemia/lymphomas. Overexpression of Dll4 had little stimulatory effect on myeloid development, although Notch1 expression has been shown in murine hematopoietic precursor cells,16 cells in the monocyte/macrophage lineage,17 and human CD34+ cells.18,19 Clearly, ectopic overexpression of Dll4 suppresses hematopoiesis in the BM and also enhances extramedullary hematopoietic activities in the spleen and other organs. Such a shift of hematopoiesis from the BM to extramedullary sites was seen as early as 4 weeks after BMT. Whether suppression of hematopoiesis in BM is a direct effect of the action of Dll4 on Notch1 and/or Notch4 or a secondary effect resulting from changes in the BM microenvironment is unclear. Several studies have suggested that Notch1 influences the lineage
decision of uncommitted T-cell precursors.20-22 That is, Notch1 activation favors the development of CD8 versus CD4 T cell and
Submitted October 19, 2000; accepted August 16, 2001.
The authors are employees of Amgen Inc.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Xiao-Qiang Yan, Amgen Inc 15-2-B, One Amgen Center Dr, Thousand Oaks, CA 91320; e-mail: xyan{at}amgen.com.
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Artavanis TS, Rand MD, Lake RJ.
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Pear WS, Aster JC, Scott ML, et al.
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© 2001 by The American Society of Hematology.
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P. A. Zweidler-McKay, Y. He, L. Xu, C. G. Rodriguez, F. G. Karnell, A. C. Carpenter, J. C. Aster, D. Allman, and W. S. Pear Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies Blood, December 1, 2005; 106(12): 3898 - 3906. [Abstract] [Full Text] [PDF]
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S. Hoflinger, K. Kesavan, M. Fuxa, C. Hutter, B. Heavey, F. Radtke, and M. Busslinger Analysis of Notch1 Function by In Vitro T Cell Differentiation of Pax5 Mutant Lymphoid Progenitors J. Immunol., September 15, 2004; 173(6): 3935 - 3944. [Abstract] [Full Text] [PDF]
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M. Ciofani, T. M. Schmitt, A. Ciofani, A. M. Michie, N. Cuburu, A. Aublin, J. L. Maryanski, and J. C. Zuniga-Pflucker Obligatory Role for Cooperative Signaling by Pre-TCR and Notch during Thymocyte Differentiation J. Immunol., May 1, 2004; 172(9): 5230 - 5239. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
) and mouse no. 21 digested with
SpeI shows that the animal contained one major (a)
and one minor clone (b).
TCR usage and also modulates T-cell versus B-cell lineage commitment. In the Dll4-overexpressing mice, we
showed small absolute and relative numbers of B220+ cells
in the lymph nodes, BM, spleen, and PB, suggesting a block in B-cell
development. We demonstrated that Dll4 overexpression resulted in accumulation of immature CD4+CD8+ T
cells in BM, PB, lymph nodes, and spleen and reduction of
CD4+CD8