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HEMATOPOIESIS
From the Partners AIDS Research Center and MGH Cancer
Center, Massachusetts General Hospital, Harvard Medical School, Boston,
MA.
Hematopoietic stem cells sequentially pass through a series of
decision points affecting self-renewal or lineage-specific differentiation. Notch1 receptor is a known modulator of
lineage-specific events in hematopoiesis that we assessed in the
context of in vivo stem cell kinetics. Using RAG-1 Hematopoiesis involves highly regulated
proliferation and differentiation during which a small number of
multipotent stem cells give rise to a large number of more
differentiated progeny. The stem cell pool is relatively quiescent and
cytokine resistant, whereas the cytokine-responsive progenitor pool is
highly proliferative. To prevent the exhaustion of the stem cell
compartment, the proliferative activity of hematopoietic stem cells is
tightly restricted. The molecular mechanisms, however, regulating the
self-renewal and differentiation of hematopoietic stem cells are not
well defined.
Members of the Notch family play critical roles in the determination of
cell fates and maintenance of differentiation status of cells in many
developmental systems (for reviews, see Artavanis-Tsakonas et
al,1 Artavanis-Tsakonas et al,2 and Milner
and Bigas3). Four mammalian Notch homologs (Notch1-4) have
been defined.4-8 The Notch genes encode large, highly
conserved type 1 transmembrane glycoprotein receptors composed of a
series of iterated structural motifs, including epidermal growth factor
(EGF)-like repeats and an intracellular ankyrinlike repeat region that
is critical for downstream signaling events.1 Physiologic
activation of Notch signaling is initiated by binding of Notch ligands,
such as Jagged1, Jagged2 and Delta, that are also transmembrane
proteins.9-13 Ligand binding leads to proteolytic cleavage
that results in the transport of the intracellular domain of Notch to
the nucleus, where Notch behaves as a transcriptional
activator.14-16
The Notch human homologue (translocation-associated Notch1) was
discovered as the t(7;9) reciprocal translocation associated with
T-cell lymphoblastic leukemia.17 This constituted the
first evidence of Notch involvement in the hematopoietic compartment and also the first indication of its oncogenic potential. The rearrangement joins portions of Notch1 and T-cell receptor- A number of studies support a broad physiologic role of Notch in the
regulation of hematopoiesis. Notch1 is expressed in bone marrow
precursor cells19 as well as in peripheral blood T and B
lymphocytes, monocytes, and neutrophils,3 whereas Notch
ligands are expressed in bone marrow stromal cells, fetal liver, and
thymus.20-23 As in other tissues, Notch seems to play 2 distinct roles in the hematopoietic system. Notch participates in cell
fate decisions within progenitor populations,24-27 and
Notch inhibits the differentiation of hematopoietic progenitors.
Transduction by a retrovirus encoding a constitutively activated Notch1
or activation of Notch1 with specific ligands resulted in the
inhibition of granulocytic differentiation and preservation of a more
immature phenotype in the murine cell line 32D, the human cell line
HL-60, and in primary murine and human myeloid progenitor
cells.20-22,28-32 Further, Varnum-Finney and
colleagues demonstrated that activated Notch1 can result in the in
vitro outgrowth of cell lines with multipotential, consistent with an
ability to immortalize stem cells.33
To determine whether activation of Notch influences stem cell function,
we transduced murine Sca1+lin Cells and cell culture
Human embryonic kidney-derived 293T cells were grown in Dulbecco
modified Eagle medium (DMEM) supplemented with 10% fetal calf serum
(FCS), 100 U/mL penicillin, 100 U/mL streptomycin, and 2 mM
L-glutamine (Gibco, BRL, Rockville, MD).
Retroviral vectors and constructs
Retroviral production and transduction The MSCV-GFP vectors were cotransfected into 293T cells using a calcium phosphate precipitation method34,37 with pKat, encoding the gag and pol proteins, and pCMV-VSV-G, a plasmid encoding the vesicular stomatitis virus G-glycoprotein (VSV-G).30 Supernatant containing VSV-G pseudotyped retroviruses was collected at 24 and 48 hours after the beginning of transfection and was used for the transduction of murine Sca1+lin bone marrow cells.
Murine Sca1+lin Colony-forming assay This assay was used to measure the progenitor cell frequency (colony-forming cell [CFC]) as previously described.38 Murine SCF was used in this study instead of human SCF and cells were plated at only 500 cells/mL.Long-term culture with limiting dilutions To quantify the stem cells in the transduced Sca1+lin population, we adapted the
cobblestone area forming cell (CAFC assay)39 with
minor modifications as described previously.38 To measure long-term culture (LTC)-initiating cells (LTC-IC) the
semisolid, cytokine-containing methylcellulose medium for CFC
was overlaid into the wells at week 5 and the colonies were counted at
day 10. A limiting dilution analysis software program (Maxrob, kindly provided by Dr Julian Down, Biotransplant, Charlestown, MA) was used to calculate the frequency of LTC-ICs in the cell population.
Competitive repopulation assay The competitive repopulation assay (CRA) was used to evaluate the repopulation ability of the transduced Sca1+lin cell population in irradiated
recipient mice.40,41 Recipient animals (C57BL/6-Ly5.1,
female; Jackson Laboratories) were irradiated with a single dose of 10 Gy 12 to 16 hours before transplantation. The transduced
Sca1+lin donor cells were obtained from 8- to
10-week-old male C57BL/6 RAG-1/ mice (Jackson
Laboratories) and prepared as above. All leukocytes of these mice are
Ly5.2+. Congenic competitive bone marrow cells (Ly5.1) were
prepared as single-cell suspension from male mice. A mixture of the
transduced Sca1+lin RAG-1/
cells (2000 or 3400) along with a radioprotective dose of congenic Ly5.1 bone marrow cells (1.5 × 105) were resuspended in
Medium 199 and intravenously injected into the lateral tail vein of
lethally irradiated Ly5.1 female recipients (n = 5 for each group).
The mice were killed at 1.5 (second experiment) and 5 months (first
experiment) and bone marrow cells were prepared from those mice and
analyzed by flow cytometry.
Serial bone marrow transplantation Serial bone marrow transplantation was used to evaluate the ability of stem cells to self-renew. The transplanted mice of the CRA were killed at 1.5 (second experiment) and 5 (first experiment) months and the bone marrow was prepared from those mice. New female recipient mice (n = 5/group) were lethally irradiated and transplanted with 4 × 106 mononuclear bone marrow cells of the killed animals by injection in lateral tail veins. Blood from second recipients was analyzed by flow cytometry every 2 weeks.Flow cytometric analysis Flow cytometry was used to quantify the hematopoietic cells at different stages in the peripheral blood and the bone marrow of the transplanted animals (CRA). Bone marrow nucleated cells were labeled with the leukocyte antibodies Ly5.1-phycoerythrin (PE) and Ly5.2-biotin (Pharmingen), lineage antibodies (CD3-peridinin chlorophyll protein [PerCP], CD4-PE, B220-PE, Ter119-PE, [Pharmingen]), CD8-Tri, Gr-1-Tri, Mac1-PE (Caltag), stem cell markers (Sca1-Tri and PE, c-kit-Tri [Caltag]), and lymphoid markers (CD19-PE, CD2430F1-biotin, CD25-PE, CD43-PE, BP-1-PE, NK1.1[PK136]-PE, IL-7-R-PE [Pharmingen]). To quantify the enriched stem cell phenotype (Sca1+lin) in
the animals receiving transplants, bone marrow cells were stained with
biotinylated lineage antibodies (CD3, Ter119 [Pharmingen], CD4, CD8,
B220, Gr-1, and Mac1 [Caltag]) and Sca1-Tri (Caltag). The cells were
analyzed after labeling with the secondary antibody streptavidin-allophycocyanin (APC; Becton Dickinson). Intracellular staining of Notch1 was performed by using a saponin
permeabilization of the cells after fixing in 1%
paraformaldehyde-PBS. The cells were incubated with polyclonal rabbit
antibodies against a portion of the intracellular domain of Notch1
(amino acids 1763-1877)23 for 30 minutes at room
temperature. Cells were then washed twice and incubated with the
monoclonal PE-conjugated goat antirabbit antibody (Sigma; 1 µg/mL).
For the measurement of bromodeoxyuridine (BrdU) incorporation in vivo, mice were injected intraperitoneally with 50 mg/kg BrdU 20 hours prior to bone marrow harvest. The cells were fixed and permeabilized in 2% paraformaldehyde/0.25% saponin PBS and stained with anti-BrdU (Becton Dickinson). The stained cell samples were analyzed on a FACScalibur cytometer (Becton Dickinson). Statistical analysis The significance of the difference between groups in the in vitro and in vivo experiments were evaluated by analysis of variance followed by a one-tailed Student t test.
Retroviral expression of activated Notch1 in murine
Sca1+lin  E) with potent transactivating
ability,18,34 were cloned into MSCV-GFP, a vector that
allows coexpression of subcloned cDNAs and GFP from a single
bicistronic mRNA transcript.30
To investigate the effects of Notch1 activation on the differentiation
of primitive hematopoietic cells, we used primary
Sca1+lin The transduction efficiency of murine bone marrow
Sca1+lin
Activated Notch1 in murine RAG-1 cells (500-3500 cells/animal)
expressing activated Notch1 (ICN or E) along with competitive bone
marrow cells developed a CD4+CD8+ T-cell
leukemia (data not shown). To better evaluate the impact of Notch1
expression in hematopoietic development, we studied the effect of
activated Notch1 in RAG-1/ bone marrow stem cells. In
the absence of RAG-1, maturation of T or B cells beyond early antigen
receptor rearrangement is prohibited.35 We transplanted
RAG-1/ Sca1+lin cells
expressing activated Notch1 into lethally irradiated C57BL/6 recipients
(n = 5) along with competitive bone marrow cells. None of the animals
receiving a transplant developed a T-cell leukemia up to 8 months after
transplantation. Neither CD3+ nor CD4+ or
CD8+ bone marrow cells could be detected in the
Ly5.2+ cell population by flow cytometry. The block in the
lymphocyte development in Notch1 overexpressing RAG-1/
stem cells appears to be sufficient to prevent the induction of T-cell
leukemias in animals receiving transplants and is consistent with a
specific differentiation stage required for Notch1-associated leukemias. These data permitted us to use the RAG-1/
background to assess the impact of Notch1 activation in the stem cell
compartment in vitro and in vivo.
Activated Notch1 inhibits the differentiation of murine
RAG-1 bone marrow cells from C57BL/6
RAG-1/ mice transduced with MSCV-ICN/GFP or
MSCV-E/GFP showed a significantly lower number of CFCs compared with
Sca1+lin cells transduced with the control
vector (Figure 2A). Although the CFCs
were reduced in number by cells expressing activated Notch1, the
colonies generated had a larger and more homogeneous phenotype
resembling high proliferative potential cells (Figure 2B). The lower
number of CFCs and the colony morphology suggest, but do not definitely
prove, a more primitive cell type consistent with an inhibition of
differentiation. The reduction in colony number was more distinct in
MSCV-E/GFP-transduced cells than in MSCV-ICN/GFP-transduced cells
in comparison to the control vector-transduced cells. The relative
potency of E compared with ICN suggests that the degree of effect
corresponds to the degree of transactivating ability of the Notch1
construct.
To more accurately quantify the stem cell frequency in the transduced
Sca1+lin We next validated that the effect of activated Notch1 on the
differentiation of hematopoietic stem cells was not unique to the
RAG-1 Activated Notch1 increases the stem cell pool in vivo To assess the correlation of the in vitro phenomena with in vivo stem cell function, we evaluated activated Notch1-expressing cells in repopulation and long-term engraftment experiments. We performed a CRA in which 2000 Notch1-transduced Sca1+lin bone
marrow cells from Ly5.2+ RAG-1/ mice were
transplanted along with a competitive population of 1.5 × 105 mononuclear Ly5.1+ bone marrow
cells into lethally irradiated female Ly5.1+ recipients.
Monoclonal antibodies recognizing Ly5.2 permit clear distinction among
congenic strains of C57BL/6 mice.
The animals were killed 5 months after transplantation to
evaluate the differentiation status of the transplanted cells in the
bone marrow. The Ly5.2+ Sca1+lin
Notably, a significantly higher fraction of
Sca1+lin
To evaluate if the stem cell expansion is caused by altered cell
cycle kinetics, we measured the BrdU incorporation into
Sca1+lin Activated Notch1 enhances stem cell self-renewal in vivo To further define the impact of Notch1 activation on stem cells, we sought to determine if stem cell self-renewal was affected in vivo using sequential bone marrow transplantation. Bone marrow from 5 animals per group transplanted with Notch1-activated Sca1+lin cells or control cells from
RAG-1/ mice were retransplanted into lethally
irradiated recipients 6 weeks after the first transplantation. To
measure the self-renewal capacity of the transduced stem cells, we
transplanted bone marrow cells containing equal numbers of total
Sca1+linGFP+Ly5.2+
cells. The secondarily transplanted animals were permitted to engraft
for 5 months prior to analysis by flow cytometry of the bone marrow.
Decrease of Ly5.2+ and
Ly5.2+GFP+Sca1+lin
cells in the bone marrow in animals transplanted with control vector-transduced bone marrow cells was consistent with hematopoietic exhaustion. Ly5.2+ cells dropped from 11.04% ± 5.4% in
the first transplant to 0.06% ± 0.017% in the second transplant;
similarly, Sca1+lin in the
Ly5.2+GFP+ cell population dropped from
2.51% ± 1.23% (total 69 392 ± 36 247 cells) in the first
transplant to undetectable in the second transplant. In marked
contrast, Ly5.2+ cells and
Sca+lin stem cells expressing activated
Notch1 increased dramatically in the bone marrow of the secondary
recipients. The Ly5.2+ cells were raised from
3.16% ± 0.96% in the first transplant to 34.5% ± 8.5% in the
second transplant. Sca1+lin cells in the
Ly5.2+GFP+ cell population increased from
10.9% ± 6.34% in the first transplant to 24.7% ± 12.5% in the
second transplant. Of particular note, the total number of
Sca1+lin cells expressing activated Notch1
increased 11-fold in the secondary recipients in the presence of
activated Notch1 in comparison to the first transplant (from
73 402 ± 35 007 to 839 159 ± 292 539; P = .01;
Figure 4E). A second experiment transplanting bone marrow into
secondary recipients 5 months after the first transplantation confirmed
these results as measured by flow cytometric analysis of the peripheral
blood 10 weeks after the second transplantation. These data indicate
that activated Notch1 is capable of enlarging the stem cell pool
in vivo by enhanced self-renewal in serially transplanted animals.
Activated Notch1 enhances early lymphoid lineage differentiation in vivo Five months after transplantation, the bone marrow of animals transplanted with Notch1 overexpressing Sca1+lin RAG-1/ cells
demonstrated a 7-fold higher fraction of B220+ cells in the
GFP+Ly5.2+ population (Figure 3A;
P = .03 MSCV-ICN/GFP versus control). These cells were
CD43+, CD24, BP-1, and
CD19, suggesting an early B-cell population as defined by
Hardy et al45 as fraction A in their scheme of B-cell
development. However, all these B220+CD19
cells expressed NK1.1 but not CD25 defining them as NK progenitor cells
as described by Rolink et al46 (Figure
5A,B). In contrast, B220+
cells in the GFP+Ly5.2+ bone marrow of animals
transplanted with control vector-transduced cells were mainly
CD19+, defining them as B cells (Figure 5B). These data
demonstrate an expansion of an early NK progenitor population
(P = .002) and a block in B-cell differentiation
(P = .01) by activated Notch1 (Figure 5C). The measurement
of in vivo BrdU incorporation into B220+NK1.1+
cells expressing activated Notch1 revealed no significant difference compared with controls indicating that the increase in NK progenitors was not due to excess proliferation of that population
(4.7% ± 1.2% MSCV-ICN/GFP verus 6.2% MSCV-GFP). In addition,
CD25+CD44+ cells representing an immature
T-cell population (reviewed in Godfrey and Zlotnik47) were
increased 8-fold in the GFP+Ly5.2+ cell
population compared with the bone marrow of animals transplanted with
control vector overexpressing stem cells (Figure 5D;
P = .01 MSCV-ICN/GFP versus control). Further, analysis
for an IL-7R+lin population in
GFP+ cells demonstrated a marked increase in the context of
activated Notch1 expression (MSCV-ICN/GFP 8.7% versus MSCV-GFP 0.3%).
These cells were mainly c-kit+Sca1+ (MSCV-GFP
64%, MSCV-ICN/GFP 85%) characterizing this population as common
lymphoid progenitors as defined by Kondo et al48 (Figure 6A).
Although the absolute numbers of differentiated cells was diminished in the context of Notch activation, there was a disproportionate decrease in myeloid versus lymphoid cells. The proportion and total number of cells expressing myeloid differentiation markers (Gr-1, Ter119, and Mac-1) were reduced (Figure 3B). The relative decrease was substantially greater for myeloid than lymphoid cells (Figure 6B). These data, coupled with the BrdU data indicating that lymphoid cell numbers are not increased due to excessive proliferation, strongly support preferential lymphoid lineage choice. However, preferential increase in survival time of lymphoid cells cannot be excluded as a potential mechanism to account for the results.
Members of the Notch family have been shown to maintain an immature precursor phenotype and affect lineage outcome in a number of developmental and differentiation systems.10,11,49,50 A role for the Notch1 pathway in the regulation of hematopoiesis has been shown by several in vitro studies demonstrating the inhibitory effects of Notch1 on the differentiation of hematopoietic progenitors.20-22,28-32 The data presented here indicate that, like its effect in other developmental systems, Notch1 affects primitive hematopoiesis in 2 ways: increasing stem cell self-renewal and affecting lineage outcome. The RAG-1 The entry of stem cells into the cell cycle is generally thought to result in either self-renewal, apoptosis, or progression down a line of differentiation, entering the progenitor cell pool. The relative balance between these asymmetric events is likely to shift under varying circumstances, for example, during ontogeny as an organism moves from early development, when expansion of the stem cell pool is necessary, to maturation when large numbers of differentiated cells are required. In adulthood, it is less clear, but bone marrow transplantation suggests that self-renewal may be enhanced under specific conditions. Mechanisms modulating the balance between self-renewal versus entrance into a differentiation program are poorly understood and our data raise the possibility that Notch1 may provide one such mechanism. Notch1 activation enhanced self-renewal, increased the stem cell pool, and diminished more mature elements. These results complement those reported by Varnum-Finney et al33 in which in vitro immortalized clones of multipotent cells were generated by activating Notch1. Differences between these studies include our data demonstrating a population effect, whereas the Varnum-Finney results report clones emerging from a population. Our data also define that expansion of the stem cell pool occurs in vivo and is further manifest as enhanced self-renewal without emergence of a leukemic population. Although Notch1 appears to affect the balance toward a more primitive phenotype, there is not an absolute block in differentiation capability. The increase in stem cell numbers induced by activated Notch1 appears to be quite distinct from a similar increase noted by other defined molecular regulators of stem cell kinetics. We previously noted that inhibition of p21Cip1 also increased the size of the stem cell pool.38 Yet in the absence of p21Cip1, stem cell self-renewal was diminished and the increased population of stem cells was not at the expense of more mature descendants. The p21Cip1 null genotype was accompanied by near-normal peripheral blood cell populations, reflective of the predominant function of p21Cip1 in restricting cell cycle entry of the stem cell compartment with less profound effects on the kinetics of other populations. In contrast, Notch1 activation, which has been reported to have no effect on overall cell cycle length in hematopoietic progenitors,30 increased stem cell numbers and self-renewal while reducing more mature populations. An additional mechanism for stem cell expansion is altered sensitivity to apoptosis induction as demonstrated in mice overexpressing BCL-2.51 Therefore, a similar outcome of increased stem cell numbers may be induced by altering cell cycle (p21Cip1) or apoptosis (BCL-2) or influencing the self-renewal versus differentiation choice (Notch1). Potentially complementary strategies for stem cell expansion are thereby suggested. In addition to the effect on self-renewal versus differentiation, Notch1 appears to have an impact on the proposed binary lymphoid versus myeloid choice made as primitive cells undertake a differentiation pathway. Prior studies with Notch activation have been limited in evaluating primitive hematopoietic populations in vivo due to the rapid emergence of T cell leukemia24,34 (and S.S., unpublished observations, 2000). The use of stem cells derived from animals engineered to be RAG-1 deficient abrogated development of leukemia. This finding both defined a differentiation stage-specific role of Notch1 in leukemogenesis (post-T-cell receptor rearrangement) and permitted evaluation of events occurring early in lymphoid differentiation. Our data indicate a previously unassigned activity of Notch1 in early
lymphoid lineage commitment, promoting early lymphoid differentiation
with an increase in common lymphoid progenitors. Further, the increased
fraction of B220+NK1.1+, which were
CD19 The decline in myeloid colonies (CFCs) and granulocytes and erythroid
cells we observed is similar to the in vitro data presented by Milner
et al.28 Other studies have not noted myeloid effects, but
systems were used in which changes in the myeloid system would be
difficult to observe (eg, the conditional Notch1 knockout dependent on
an interferon promotor53 or the rapid induction of
leukemia24). The decrease in myeloid cells we documented,
accompanied by the increase in lymphoid precursor cells, is consistent
with the hypothesis that lineage choice may be influenced by Notch1
activation favoring lymphoid commitment. The absence of increased BrdU
staining in this progenitor population argues against Notch1 expanding
already committed lymphoid cells. Rather, the relative reduction in
myeloid cells supports an effect of Notch on lineage choice at the
lymphoid-myeloid juncture. However, preferential changes in lymphoid
survival time over myeloid cell survival cannot be excluded as an
alternative explanation for the data. The model that lineage choice is
affected is highly consistent with prior studies demonstrating an
impact of Notch on other binary differentiation events in hematopoiesis such as Taken together, our data support a model in which Notch1 functions at multiple levels in the hematopoietic cascade with distinct outcomes dependent on the differentiation stage at which it is activated. In the primitive populations we studied, Notch1 facilitates self-renewal of hematopoietic stem cells by impeding exit from the stem cell pool and influences lineage outcome on a very primitive level, affecting the relative abundance of lymphoid populations. Analyzing the molecular accompaniments of Notch1 functional activity may provide insight into determinants of stem cell self-renewal and lineage commitment and will be of considerable interest. It should be noted, however, that the data presented here are obtained from an overexpression system and require verification using more physiologic mechanisms of Notch1 activation. The use of Notch ligands to increase stem cell expansion and favor subsequent lymphoid differentiation has substantial appeal in transplantation strategies and in the context of human immunodeficiency virus disease. Controlled manipulation of the activities defined here may provide ex vivo approaches to increase stem cells and cells moving toward T-lineage maturation, highly desirable events to advance immune reconstitution after bone marrow transplantation or in the setting of acquired immunodeficiency syndrome.
The authors gratefully acknowledge the contributions of Dr Fred Preffer for flow cytometric expertise, Dr Jon Aster in reagents and careful reading of the manuscript, and Dr Ken Cohen for careful manuscript review.
Submitted September 18, 2001; accepted November 26, 2001.
Supported by National Institutes of Health grants HL45851, DK50234 (to D.T.S.), DK02761 (to T.C.), Defense Advanced Research Projects Agency (DARPA) (to D.T.S.), the Deutscher Akademischer Austauschdienst (to S.S.), Partners Investigator/Nesson Award (to N.C.), and the Richard Saltonstall Charitable Foundation (to D.T.S).
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: David T. Scadden, Massachusetts General Hospital, 149 13th St, Rm 5212D, Boston, MA 02129; e-mail: scadden.david{at}mgh.harvard.edu.
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  J.-A Kim, Y.-J. Kang, G. Park, M. Kim, Y.-O. Park, H. Kim, S.-H. Leem, I.-S. Chu, J.-S. Lee, E.-H. Jho, et al. Identification of a Stroma-Mediated Wnt/{beta}-Catenin Signal Promoting Self-Renewal of Hematopoietic Stem Cells in the Stem Cell Niche Stem Cells, June 1, 2009; 27(6): 1318 - 1329. [Abstract] [Full Text] [PDF]
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 A. Praetor, J. M. McBride, H. Chiu, L. Rangell, L. Cabote, W. P. Lee, J. Cupp, D. M. Danilenko, and S. Fong Genetic deletion of JAM-C reveals a role in myeloid progenitor generation Blood, February 26, 2009; 113(9): 1919 - 1928. [Abstract] [Full Text] [PDF]
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Y.-W. Kim, B.-K. Koo, H.-W. Jeong, M.-J. Yoon, R. Song, J. Shin, D.-C. Jeong, S.-H. Kim, and Y.-Y. Kong Defective Notch activation in microenvironment leads to myeloproliferative disease Blood, December 1, 2008; 112(12): 4628 - 4638. [Abstract] [Full Text] [PDF]
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C. S. Tremblay, F. F. Huang, O. Habi, C. C. Huard, C. Godin, G. Levesque, and M. Carreau HES1 is a novel interactor of the Fanconi anemia core complex Blood, September 1, 2008; 112(5): 2062 - 2070. [Abstract] [Full Text] [PDF]
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L. Zhou, L. W. Li, Q. Yan, B. Petryniak, Y. Man, C. Su, J. Shim, S. Chervin, and J. B. Lowe Notch-dependent control of myelopoiesis is regulated by fucosylation Blood, July 15, 2008; 112(2): 308 - 319. [Abstract] [Full Text] [PDF]
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 B. J. Thompson, V. Jankovic, J. Gao, S. Buonamici, A. Vest, J. M. Lee, J. Zavadil, S. D. Nimer, and I. Aifantis Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7 J. Exp. Med., June 9, 2008; 205(6): 1395 - 1408. [Abstract] [Full Text] [PDF]
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F. Dayyani, J. Wang, J.-R. J. Yeh, E.-Y. Ahn, E. Tobey, D.-E. Zhang, I. D. Bernstein, R. T. Peterson, and D. A. Sweetser Loss of TLE1 and TLE4 from the del(9q) commonly deleted region in AML cooperates with AML1-ETO to affect myeloid cell proliferation and survival Blood, April 15, 2008; 111(8): 4338 - 4347. [Abstract] [Full Text] [PDF]
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U. Blank, G. Karlsson, and S. Karlsson Signaling pathways governing stem-cell fate Blood, January 15, 2008; 111(2): 492 - 503. [Abstract] [Full Text] [PDF]
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J. L. Moody, S. Singbrant, G. Karlsson, U. Blank, M. Aspling, J. Flygare, D. Bryder, and S. Karlsson Endoglin Is Not Critical for Hematopoietic Stem Cell Engraftment and Reconstitution but Regulates Adult Erythroid Development Stem Cells, November 1, 2007; 25(11): 2809 - 2819. [Abstract] [Full Text] [PDF]
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Y. Chen, P. Haviernik, K. D. Bunting, and Y.-C. Yang Cited2 is required for normal hematopoiesis in the murine fetal liver Blood, October 15, 2007; 110(8): 2889 - 2898. [Abstract] [Full Text] [PDF]
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 M. J. Nemeth, L. Topol, S. M. Anderson, Y. Yang, and D. M. Bodine Wnt5a inhibits canonical Wnt signaling in hematopoietic stem cells and enhances repopulation PNAS, September 25, 2007; 104(39): 15436 - 15441. [Abstract] [Full Text] [PDF]
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 M. K. Taylor, K. Yeager, and S. J. Morrison Physiological Notch signaling promotes gliogenesis in the developing peripheral and central nervous systems Development, July 1, 2007; 134(13): 2435 - 2447. [Abstract] [Full Text] [PDF]
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 A. Wilson, D.-L. Ardiet, C. Saner, N. Vilain, F. Beermann, M. Aguet, H. R. MacDonald, and O. Zilian Normal Hemopoiesis and Lymphopoiesis in the Combined Absence of Numb and Numblike J. Immunol., June 1, 2007; 178(11): 6746 - 6751. [Abstract] [Full Text] [PDF]
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 V. Bolos, J. Grego-Bessa, and J. L. de la Pompa Notch Signaling in Development and Cancer Endocr. Rev., May 1, 2007; 28(3): 339 - 363. [Abstract] [Full Text] [PDF]
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C. M. Flynn and D. S. Kaufman Donor cell leukemia: insight into cancer stem cells and the stem cell niche Blood, April 1, 2007; 109(7): 2688 - 2692. [Abstract] [Full Text] [PDF]
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N. Chadwick, M. C. Nostro, M. Baron, R. Mottram, G. Brady, and A.-M. Buckle Notch Signaling Induces Apoptosis in Primary Human CD34+ Hematopoietic Progenitor Cells Stem Cells, January 1, 2007; 25(1): 203 - 210. [Abstract] [Full Text] [PDF]
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U. Blank, G. Karlsson, J. L. Moody, T. Utsugisawa, M. Magnusson, S. Singbrant, J. Larsson, and S. Karlsson Smad7 promotes self-renewal of hematopoietic stem cells Blood, December 15, 2006; 108(13): 4246 - 4254. [Abstract] [Full Text] [PDF]
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S. Chiba Concise Review: Notch Signaling in Stem Cell Systems Stem Cells, November 1, 2006; 24(11): 2437 - 2447. [Abstract] [Full Text] [PDF]
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M. Garcia-Peydro, V. G. de Yebenes, and M. L. Toribio Notch1 and IL-7 Receptor Interplay Maintains Proliferation of Human Thymic Progenitors while Suppressing Non-T Cell Fates J. Immunol., September 15, 2006; 177(6): 3711 - 3720. [Abstract] [Full Text] [PDF]
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R. F. de Pooter, T. M. Schmitt, J. L. de la Pompa, Y. Fujiwara, S. H. Orkin, and J. C. Zuniga-Pflucker Notch Signaling Requires GATA-2 to Inhibit Myelopoiesis from Embryonic Stem Cells and Primary Hemopoietic Progenitors J. Immunol., May 1, 2006; 176(9): 5267 - 5275. [Abstract] [Full Text] [PDF]
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X. Yu, J. K. Alder, J. H. Chun, A. D. Friedman, S. Heimfeld, L. Cheng, and C. I. Civin HES1 Inhibits Cycling of Hematopoietic Progenitor Cells via DNA Binding Stem Cells, April 1, 2006; 24(4): 876 - 888. [Abstract] [Full Text] [PDF]
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L. M. Kamminga, L. V. Bystrykh, A. de Boer, S. Houwer, J. Douma, E. Weersing, B. Dontje, and G. de Haan The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion Blood, March 1, 2006; 107(5): 2170 - 2179. [Abstract] [Full Text] [PDF]
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 J.-Y. Rho, K. Yu, J.-S. Han, J.-I. Chae, D.-B. Koo, H.-S. Yoon, S.-Y. Moon, K.-K. Lee, and Y.-M. Han Transcriptional profiling of the developmentally important signalling pathways in human embryonic stem cells Hum. Reprod., February 1, 2006; 21(2): 405 - 412. [Abstract] [Full Text] [PDF]
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J. Huang, K. P. Garrett, R. Pelayo, J. C. Zuniga-Pflucker, H. T. Petrie, and P. W. Kincade Propensity of Adult Lymphoid Progenitors to Progress to DN2/3 Stage Thymocytes with Notch Receptor Ligation J. Immunol., October 15, 2005; 175(8): 4858 - 4865. [Abstract] [Full Text] [PDF]
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 C. E. Burns, D. Traver, E. Mayhall, J. L. Shepard, and L. I. Zon Hematopoietic stem cell fate is established by the Notch-Runx pathway Genes & Dev., October 1, 2005; 19(19): 2331 - 2342. [Abstract] [Full Text] [PDF]
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L. M. Sarmento, H. Huang, A. Limon, W. Gordon, J. Fernandes, M. J. Tavares, L. Miele, A. A. Cardoso, M. Classon, and N. Carlesso Notch1 modulates timing of G1-S progression by inducing SKP2 transcription and p27Kip1 degradation J. Exp. Med., July 5, 2005; 202(1): 157 - 168. [Abstract] [Full Text] [PDF]
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S. Stier, Y. Ko, R. Forkert, C. Lutz, T. Neuhaus, E. Grunewald, T. Cheng, D. Dombkowski, L. M. Calvi, S. R. Rittling, et al. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size J. Exp. Med., June 6, 2005; 201(11): 1781 - 1791. [Abstract] [Full Text] [PDF]
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J. S. Dando, M. Tavian, C. Catelain, S. Poirault, A. Bennaceur-Griscelli, F. Sainteny, W. Vainchenker, B. Peault, and E. Lauret Notch/Delta4 Interaction in Human Embryonic Liver CD34+ CD38- Cells: Positive Influence on BFU-E Production and LTC-IC Potential Maintenance Stem Cells, April 1, 2005; 23(4): 550 - 560. [Abstract] [Full Text] [PDF]
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S. J. C. Mancini, N. Mantei, A. Dumortier, U. Suter, H. R. MacDonald, and F. Radtke Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation Blood, March 15, 2005; 105(6): 2340 - 2342. [Abstract] [Full Text] [PDF]
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A. Robert-Moreno, L. Espinosa, J. L. de la Pompa, and A. Bigas RBPj{kappa}-dependent Notch function regulates Gata2 and is essential for the formation of intra-embryonic hematopoietic cells Development, March 1, 2005; 132(5): 1117 - 1126. [Abstract] [Full Text] [PDF]
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R. N. La Motte-Mohs, E. Herer, and J. C. Zuniga-Pflucker Induction of T-cell development from human cord blood hematopoietic stem cells by Delta-like 1 in vitro Blood, February 15, 2005; 105(4): 1431 - 1439. [Abstract] [Full Text] [PDF]
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R. van Os, L. M. Kamminga, and G. de Haan Stem Cell Assays: Something Old, Something New, Something Borrowed Stem Cells, December 1, 2004; 22(7): 1181 - 1190. [Abstract] [Full Text] [PDF]
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J. J. Schuringa, K. Wu, G. Morrone, and M. A.S. Moore Enforced Activation of STAT5A Facilitates the Generation of Embryonic Stem-Derived Hematopoietic Stem Cells That Contribute to Hematopoiesis In Vivo Stem Cells, December 1, 2004; 22(7): 1191 - 1204. [Abstract] [Full Text] [PDF]
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B. K. Hadland, S. S. Huppert, J. Kanungo, Y. Xue, R. Jiang, T. Gridley, R. A. Conlon, A. M. Cheng, R. Kopan, and G. D. Longmore A requirement for Notch1 distinguishes 2 phases of definitive hematopoiesis during development Blood, November 15, 2004; 104(10): 3097 - 3105. [Abstract] [Full Text] [PDF]
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S. Karlsson Stem cell expansion: success and complexities Blood, October 15, 2004; 104(8): 2210 - 2211. [Full Text] [PDF]
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S. M. Vercauteren and H. J. Sutherland Constitutively active Notch4 promotes early human hematopoietic progenitor cell maintenance while inhibiting differentiation and causes lymphoid abnormalities in vivo Blood, October 15, 2004; 104(8): 2315 - 2322. [Abstract] [Full Text] [PDF]
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I. Maillard, A. P. Weng, A. C. Carpenter, C. G. Rodriguez, H. Sai, L. Xu, D. Allman, J. C. Aster, and W. S. Pear Mastermind critically regulates Notch-mediated lymphoid cell fate decisions Blood, September 15, 2004; 104(6): 1696 - 1702. [Abstract] [Full Text] [PDF]
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J. J. Schuringa, K. Y. Chung, G. Morrone, and M. A.S. Moore Constitutive Activation of STAT5A Promotes Human Hematopoietic Stem Cell Self-Renewal and Erythroid Differentiation J. Exp. Med., September 7, 2004; 200(5): 623 - 635. [Abstract] [Full Text] [PDF]
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M. Iwata, N. Awaya, L. Graf, C. Kahl, and B. Torok-Storb Human marrow stromal cells activate monocytes to secrete osteopontin, which down-regulates Notch1 gene expression in CD34+ cells Blood, June 15, 2004; 103(12): 4496 - 4502. [Abstract] [Full Text] [PDF]
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 D. B. Sykes and M. P. Kamps E2a/Pbx1 Induces the Rapid Proliferation of Stem Cell Factor-Dependent Murine Pro-T Cells That Cause Acute T-Lymphoid or Myeloid Leukemias in Mice Mol. Cell. Biol., February 1, 2004; 24(3): 1256 - 1269. [Abstract] [Full Text] [PDF]
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 R. Qi, H. An, Y. Yu, M. Zhang, S. Liu, H. Xu, Z. Guo, T. Cheng, and X. Cao Notch1 Signaling Inhibits Growth of Human Hepatocellular Carcinoma through Induction of Cell Cycle Arrest and Apoptosis Cancer Res., December 1, 2003; 63(23): 8323 - 8329. [Abstract] [Full Text] [PDF]
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B. Varnum-Finney, C. Brashem-Stein, and I. D. Bernstein Combined effects of Notch signaling and cytokines induce a multiple log increase in precursors with lymphoid and myeloid reconstituting ability Blood, March 1, 2003; 101(5): 1784 - 1789. [Abstract] [Full Text] [PDF]
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 T. Reya Regulation of Hematopoietic Stem Cell Self-Renewal Recent Prog. Horm. Res., January 1, 2003; 58(1): 283 - 295. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
(TCR-
T-cell, CD4 versus CD8 
two mouse Notch homologues coexpressed in a wide variety of tissues.
Exp Cell Res.
1993;204:364-372