Oncogene (2008) 27, 7003–7017
& 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00
www.nature.com/onc
REVIEW
Upsides and downsides to polarity and asymmetric cell division in leukemia
ED Hawkins1 and SM Russell1,2
1
Immune Signalling Laboratory, Cancer Immunology, Research Division, Peter MacCallum Cancer Centre, East Melbourne,
Victoria, Australia and 2Centre for MicroPhotonics, Swinburne University of Technology, Faculty of Engineering and Industrial
Sciences, Hawthorn, Victoria, Australia
The notion that polarity regulators can act as tumor
suppressors in epithelial cells is now well accepted. The
function of these proteins in lymphocytes is less well
explored, and their possible function as suppressors of
leukemia has had little attention so far. We review the
literature on lymphocyte polarity and the growing
recognition that polarity proteins have an important
function in lymphocyte function. We then describe
molecular relationships between the polarity network
and signaling pathways that have been implicated in
leukemogenesis, which suggest mechanisms by which the
polarity network might impact on leukemogenesis. We
particularly focus on the possibility that disruption of
polarity might alter asymmetric cell division (ACD), and
that this might be a leukemia-initiating event. We also
explore the converse possibility that leukemic stem cells
might be produced or maintained by ACD, and therefore
that Dlg, Scribble and Lgl might be important regulators
of this process.
Oncogene (2008) 27, 7003–7017; doi:10.1038/onc.2008.350
Keywords: leukemia; lymphoma; Scribble; asymmetric
cell divison; polarity; self-renewal
Introduction
There is a growing recognition that polarity has an
important function in the initiation and progression of
solid tumors, based partly on observations that polarity
is lost in malignant epithelial tumors, and that disruptions in polarity genes can lead to epithelial tumors in
the fly and in mammals (Humbert et al., 2003; Bilder,
2004; Hezel and Bardeesy, 2008; Humbert et al., 2008;
Januschke and Gonzalez, 2008). A potential function for
polarity in leukemia is less well explored, but recent
observations have suggested that investigation into
polarity will result in important advances in our
understanding of leukemia, with potential therapeutic
implications.
Correspondence: Dr SM Russell, Immune Signalling Laboratory,
Cancer Immunology, Peter MacCallum Cancer Centre, East
Melbourne, Victoria 3002, Australia.
E-mail: [email protected]
We will discuss current knowledge of the function and
mechanisms of polarity in leukocytes, and how dysregulation of polarity might impact on leukemogenesis.
Polarity has an important function in many of the likely
cells of origin of leukemia and lymphoma, including
hematopoietic stem cells (HSCs), myeloid cells and
lymphocytes. Because polarity is best studied in mature
T cells, we utilize that knowledge as a possible basis for
broad considerations as to how polarity might impact
on different stages of leukemia progression, including
failure of differentiation, excessive proliferation, failure
of compartmentalization, and failure of normal induction of apoptosis. We address a likely role for a
relatively unexplored aspect of polarity in leukemic
cells, asymmetric cell division (ACD). With regard to
hematopoietic cells, the most convincing demonstration
of ACD is in mature T cells and is therefore not
obviously applicable to certain malignancies. However,
the concepts of ACD can perhaps be applied to other
malignancies, in particular myeloid leukemias. We
discuss how the evidence that ACD can be controlled
in non-adherent hematopoietic cells, combined with a
role for ACD in stem cell self-renewal, might suggest
a broad role in hematopoietic malignancies.
Polarity in lymphocytes
Although polarity has traditionally been studied in
epithelial and developmental progenitor cells, polarity
also regulates many physiologically important processes
in leukocytes. These include processes such as migration, targeted secretion of cytolytic granules and
cytokines, and compartmentalization of signaling to
regulate processes such as T-cell activation by antigenpresenting cells (Zigmond et al., 1981; Russell, 2008).
Although there are broad similarities in the polarization
of leukocytes and epithelial cells, there are also clear
differences between the types of polarity adopted by
leukocytes, and the cues that can initiate polarity
(Krummel and Macara, 2006; Russell, 2008). For
instance, similar to adherent cells, migrating neutrophils
and T cells have a leading edge rich in chemokine
receptors. In contrast to adherent cells where the
microtubule organizing center (MTOC) is generally at
the leading edge, in migrating leukocytes the MTOC is
at the rear (Affolter and Weijer, 2005; Russell, 2008).
Polarity and asymmetric cell division in leukemia
ED Hawkins and SM Russell
7004
In addition to migratory polarity induced by chemokines, lymphocytes can polarize during activation by
antigen-presenting cells to form an immunological
synapse, which orchestrates the signaling response.
Polarization during T-cell cytotoxicity or T-cell help
also involves the establishment of an immunological
synapse, to which the MTOC and secretory vesicles are
recruited. This specifically targets cytotoxic granules and
cytokines from the T cell to target cells (Stinchcombe
and Griffiths, 2007). Activated and migrating T cells
have a single protrusion called a uropod, which contains
adhesion receptors for interaction with other lymphocytes. Polarization is also induced by the ligation of
surface receptors, for instance by pathogens. In this
process, termed capping because the ligated surface
proteins are recruited to a single site on the lymphocyte,
the cap often aligns with the axis of polarity and occurs
at the tip of the uropod.
The wide range of different forms of polarity that
have been observed in lymphocytes perhaps reflects their
dynamic behavior, and the fact that they are not
constrained in solid tissue. Inputs that can dictate
polarity include chemokines, antigen-presenting cells
(dendritic cells, B cells, thymic epithelial cells), targets of
cytotoxic T cells, vascular endothelium, extracellular
matrix, homotypic adhesions (interactions with other
lymphocytes) and interactions with pathogens (Figure 1).
Furthermore, leukocytes often reside in sites rich in
competing cues for polarity such as the thymus (thymic
epithelial cells or chemokines; Figure 2a; Ladi et al.,
2006; Yin et al., 2007), the lymph nodes (dendritic cells
or chemokines; Figure 2d; Dustin, 2002), and might well
occur in the vascular tissue or at sites of infection
(Figures 2b and c). Thus, it is now apparent that the
form of polarity adopted by the leukocyte is an
important means by which multiple signals are integrated to determine a functional response (Bromley
et al., 2000; Oliaro et al., 2006; Heit et al., 2008).
Many recent studies have begun to elucidate the
mechanisms by which polarity is established in T cells,
and not surprisingly, there are some striking similarities
between the molecular players in epithelial and T-cell
polarity (Krummel and Macara, 2006). Tumor suppressor members of the polarity network that regulate apical
Chemokines
Homotypic
interactions
Extracellular matrix
Vascular endothelium
Pathogen (e.g.
virological synapse)
Antigen-presenting cell
T-cell
targets
Thymic epithelial cell
Figure 1 Many different cues can regulate leukocyte polarity. The leukocyte in the center can polarize (aligning the microtubule
organizing center (MTOC) and nucleus depicted, as well as cytoplasmic and surface molecules) toward each of the cues illustrated.
Polarity cues for leukemic cells might include anything that dictates polarization either of hematopoietic stem cells or of mature
lymphocytes. This could include interaction with stromal cells (for instance, in the stem cell niche of the bone marrow), interaction with
other cell types that can engage cell surface receptors to induce polarity (antigen presentation, triggers of the virological synapse,
patching and capping of surface receptors), exposure to chemokines or extracellular matrix, or homotypic interactions (Russell, 2008).
Thus, the availability of the cues in a particular location and their ability to compete with each other to dictate polarity are likely to
influence how polarity impacts on leukemogenesis.
Oncogene
Polarity and asymmetric cell division in leukemia
ED Hawkins and SM Russell
7005
a
b
Thymus
Bacterial Infection
Thymic precursors interact
with stromal factors to
progress through DN stages,
γδ T-cell differentiation and
the generatation of mature
CD4 and CD8 T cells
Neutrophils are attracted
to sites of infection by chemokines
but then prioritize attention to
bacterial infection through Pten
localization
Peripheral lymphoid
organ
HTLV-1 infection
Infection with the HTLV-1 virus
causes the development of a
polarized virological synapse.
The transmitted viral protein
Tax can also interact with polarity
proteins causing their
mislocalization
Migration along
chemokine gradient
to APC
c
d
Motile T cells follow signals on
spleen conduits and interact with
APCs. Here, an ACD generates
differentiation to effector and
memory T-cells
Figure 2 The many faces of polarity in leukocyte behavior. Different sites within the body provide different cues for polarity.
(a) Thymocytes polarize differently toward thymic epithelial cells and chemokines. (b) T cells infected with retroviruses such as human
T-cell leukemia virus (HTLV-1) and HIV form virological synapses. (c) Leukocytes at an infection site can polarize through
chemokines, and through direct interactions with target cells (for instance, to mediate secretion of cytotoxic granules) or bacterial
products. (d) T cells follow chemokine gradients to secondary lymphoid tissue, and then reorient polarity to undergo antigen
presentation.
Table 1
Proteins of the polarity complexes implicated in leukocytes
Polarity protein
Drosophila homolog
Mammalian isoforms
Tumor suppressor
in the fly
T-cell expression
T-cell
function
Scribble complex
Dlg
Scribble
Lgla
Dlg
Scribble
Lgl
Dlg1, Dlg2, Dlg3, Dlg4
Scribble
Lgl1, 2
+
+
+
Dlg1, 4
+
+
Dlg1
+
ND
Par3 complex
Par3
Par6
aPKC
Bazooka
Par6
aPKC
Par3
Par6
PKCi/l and z
a
a
a
+
+
+
a
Lgl was historically considered part of the Scribble complex based on genetic and functional evidence (Humbert et al., 2003; Kallay et al., 2006).
However, Lgl can also interact with members of the Par3 complex. The Par3 and Scribble complex exert antagonistic effects on each other in terms
of localization, and this might occur at least in part because of a molecular antagonism between aPKC and Lgl (Humbert et al., 2006). Because Dlg,
Scribble and Lgl all act similarly in terms of tumor suppression, they are considered together in this review. Although the Drosophila Par3 complex
proteins are not traditionally considered tumor suppressors, they can show tumor suppressor or oncogenic effects under certain circumstances
(Humbert et al., 2008).
basal polarity in epithelial cells are included in this list
(Table 1). Importantly, new evidence suggests that these
proteins have diverse functions in regulating basic
lymphocyte behavior. Knockdown of Scribble expression in a T-cell line abrogates migration ability and
prevents the remodeling associated with antigen presentation (Ludford-Menting et al., 2005). Discs large
(Dlg, a member of the Scribble complex) is important
for uropod formation, lipid raft and immunological
synapse composition, and for the virological synapse
induced by human T-cell leukemia virus (HTLV-1)
infection (Blot et al., 2004; Xavier et al., 2004; LudfordMenting et al., 2005; Round et al., 2005). There is also
evidence for expression of both the Crumbs and the Par
complexes in T cells (Humbert et al., 2006; Krummel
and Macara, 2006). A member of the Par complex,
aPKC, controls lymphocyte homing, migration and
scanning (Giagulli et al., 2004; Real et al., 2007). Par3
controls polarity during chemokine stimulation by
regulating the RhoGTPases, Rap1 and Rac1 (Gerard
et al., 2007). These observations indicate that the
regulation of polarity is conserved across diverse cell
types and species (Krummel and Macara, 2006; Russell,
2008).
Polarity and the polarity network in solid tumors and
leukemia
The best evidence that polarity is important in
tumorigenesis is that loss of the Scribble complex genes
(Scribble, Discs large (Dlg) and Lethal giant larvae
(Lgl)) in Drosophila leads not only to loss of epithelial
polarity but also to epithelial cancers (Humbert et al.,
2003; Lee and Vasioukhin, 2008; Humbert et al., 2008).
In addition, aPKC, which antagonizes polarity mediated
by the Scribble complex, can act as an oncogene
(Lee and Vasioukhin, 2008; Aranda et al., 2008),
suggesting that the Par complex as a whole might
Oncogene
Polarity and asymmetric cell division in leukemia
ED Hawkins and SM Russell
7006
balance the effects of the Scribble complex in tumor
suppression. Validation that Scribble, Dlg and Lgl are
also tumor suppressor genes in mammals has been
difficult. This is in part due to early lethality in knockout
mice, and also to the growing realization that these
genes are likely to act in cooperation with others, and so
will not be revealed by simple analysis of, for instance,
mutations in cancers. Despite this complexity, a growing
number of studies support the notion that mammalian
polarity proteins also act as tumor suppressors (Aranda
et al., 2008; Hezel and Bardeesy, 2008; Humbert et al.,
2008; Thomas et al., 2008). Given that the study of
how polarity affects the function of lymphocytes is a
relatively young field, it is not surprising that there has
been little consideration of how diseases of the blood
such as leukemia might be regulated by polarity
proteins. However, the literature discussed below shows
tantalizing anecdotal, morphological and functional
data to suggest that polarity might have a function in
leukemogenesis and prognosis.
How might polarity impact on leukemogenesis?
Lessons learnt from studying polarity in epithelial
tumorigenesis have paved the way for us to begin to
consider how polarity might affect leukemogenesis. The
first notions relate to the concept that a loss of polarity
leads to tumorigenesis, perhaps by altering cell–cell or
cell–matrix interactions. This is supported by substantial
evidence and continues to be an important concept in
the field (Humbert et al., 2003; Lee and Vasioukhin,
2008). A second stage of thinking relates to the concept
that epithelial cancers undergo a transition to a more
mesenchymal state that facilitates metastasis (termed
epithelial to mesenchymal transition) (see MorenoBueno et al., 2008), which might then involve a reversion
back to an epithelial morphology in the new metastatic
site (termed mesenchymal to epithelial transition)
(Thiery and Sleeman, 2006). This notion raises the
possibility that cancer progression involves not so much
loss of polarity, but changes from apicobasal polarity to
migratory potential (Thiery and Sleeman, 2006), for
which Lgl, Scribble and Dlg might have important
functions (Humbert et al., 2006; Etienne-Manneville,
2008). Finally, as discussed in detail below, it is now
thought that polarity in ACD might have very
important functions in epithelial cancer progression. In
considering possible roles for polarity in hematopoietic
malignancies, we should consider not only that similar
concepts might apply to the two cell types but also that
the architecture of hematopoietic organs might have as
important a function as the architecture of an epithelial
tissue.
As described earlier, polarity in leukocytes can be
triggered by many different cues, and can influence
many processes. Thus, disruption of polarity could
potentially regulate a number of different aspects of
disease development. The origin of leukemia is likely to
be important in considering how polarity might impact
Oncogene
on cancer initiation or progression, because both the cell
type and the site of leukemogenesis is likely to impact on
the type of polarity involved. For instance, T-cell acute
lymphoblastic leukemia (T-ALL) originates during
thymocyte development, so presumably the initial
oncogenic events occur in the thymus, where cells
polarize both in response to chemokines and antigen
presentation by thymic epithelial cells (Figure 2a) (Ladi
et al., 2006). As discussed earlier, activated T cells and
migrating T cells and neutrophils produce a single
protrusion called a uropod, which contains adhesion
receptors for interaction with other lymphocytes
(Figures 2c and d). Some leukemic cells were called
‘hand-mirror cells’ by pathologists because of evidence
for a uropod in blood smears, but with no evident
prognostic value, interest in hand-mirror cells has faded
(Norberg et al., 1977; Schumacher et al., 1979). Another
example is adult T-cell leukemia/lymphoma (ATLL)
which is caused by infection with the HTLV-1 retrovirus. Cells infected with HTLV-1 polarize to form a
virological synapse that facilitates transfer of the virus
to neighboring cells (Figure 2b). This process is
orchestrated by the viral oncogene, Tax, which can bind
directly with Dlg and Scribble, to influence proliferation
(Igakura et al., 2003; Barnard et al., 2005; Javier, 2008).
Interactions between the polarity network and signaling
pathways involved in leukemogenesis
Many of the signaling pathways that have been
implicated in leukemogenesis have the potential to
functionally interact with the polarity proteins. Indeed,
analysis in other cell types provides information on
some intriguing molecular connections between polarity
and the proteins that have been implicated as oncogenes
or tumor suppressors in leukemia, and this information
can now be exploited to produce some testable working
models. Here, we consider a partial list of candidates for
which there is some information.
Wnt
Signaling from the Wnt family of secreted lipoproteins
regulates diverse cellular processes during development,
and there is a growing recognition that Wnt has a
function in leukemogenesis (Weerkamp et al., 2006;
Staal et al., 2008). The Wnt-regulated transcription
factor, LEF1, is overexpressed in human leukemias, and
constitutive activation of LEF1 in mice leads to B-cell
lymphoblastic leukemia and acute myeloid leukemia
(AML) (Petropoulos et al., 2008). A number of
observations suggest that Wnt is important in AML
and chronic lymphocytic leukemia (Lu et al., 2004;
Mikesch et al., 2007), and abnormal methylation of Wnt
pathway components is associated with poor prognosis
in ALL patients (Roman-Gomez et al., 2007). The
central mediator of the Wnt canonical signaling pathway is the cytosolic protein b-catenin, which clearly has
a function in leukemia. b-Catenin is stabilized by BCRAbl translocation in chronic myeloid leukemia (CML)
Polarity and asymmetric cell division in leukemia
ED Hawkins and SM Russell
7007
(Coluccia et al., 2007), and its expression in AML
correlates with poor prognosis (Ysebaert et al., 2006).
Furthermore, the engineered stabilization of b-catenin
in mouse thymocytes leads to malignant transformation
(Guo et al., 2007).
Although a relationship between Wnt and lymphocyte
polarity is not yet established, the Wnt pathway
regulates polarity in many other cellular systems, for
example in Xenopus convergent extension (Tanegashima
et al., 2008) and migrating mammalian fibroblasts
(Schlessinger et al., 2007). Wnt is classically considered
the primary regulator of planar cell polarity, and there
are many interactions between the Wnt pathway and the
polarity network that support a functional relationship
between Wnt signaling and cell polarity of adherent
cells. These include the findings that the polarity
network regulates adenomatous polyposis coli localization (Etienne-Manneville and Hall, 2003; EtienneManneville et al., 2005), and that Dlg can interact with
adenomatous polyposis coli to negatively regulate
b-catenin signaling (Ishidate et al., 2000). Polarity proteins
also interact with the non-canonical, planar cell polarity
Wnt pathways, as Lgl is regulated by the essential Wnt
pathway component, Dishevelled (Dollar et al., 2005)
and Scribble and Dlg interact with Vangl2 or Strabismus (Lee et al., 2003; Montcouquiol et al., 2003).
Interestingly, the Wnt pathway also has an important
function in the polarity switch that occurs during
epithelial to mesenchymal transition in epithelial cancer
(Huber et al., 2005), and expression of b-catenin and
Scribble showed tight correlation in colorectal neoplasia
(Kamei et al., 2007). Taken together, these observations
suggest that the polarity network might also alter Wnt
signaling in leukemia development or progression.
PTEN and phosphatidylinositol signaling
Phosphatase and tensin homolog (PTEN) is a phosphatase capable of regulating both proliferation and
survival by opposing the effects of phosphotidylinositol-3-OH kinase (PI(3)K) activation. Thus, unsurprisingly, PTEN has been found to have a strong tumor
suppressor function in solid tumors and in leukemia,
and other members of this pathway also have a function
in tumorigenesis (Cully et al., 2006; Steelman et al.,
2008). Decreased phosphorylation of PTEN (which is
commonly associated with a reduction in PTEN
signaling) has been found in approximately 75% of
human AML patient samples. However, it is unlikely
that this is a direct effect of PTEN modification as
specific inactivating mutations have not been found
frequently in these human AML samples (Dahia et al.,
1999; Aggerholm et al., 2000). Downregulation of
PTEN induces ATLL-type multilobulated nuclear formation and is also associated with the cellular proliferation of malignant T-cell leukemias and lymphomas
(Fukuda et al., 2005).
PTEN regulates polarity of a number of cell types,
and directly interacts with Par3 (Li et al., 2003; von
Stein et al., 2005; Wu et al., 2007a). Spatial separation of
the PI(3)K products PtdIns(4,5)P2 and PtdIns(3,4,5)P3
is crucial for apical–basal cell polarity, where apical
targeting of PTEN regulates the accumulation of the
PI(3)K product PtdIns(4,5)P2, which in turn localizes
Cdc42 and aPKC to dictate cell polarity (Comer and
Parent, 2007; Martin-Belmonte et al., 2007). A role for
PTEN and the PI(3)K pathway is well established in
neutrophils for recruitment to infection sites and
prioritizing attention from chemokines to bacterial
products (Figure 2c) (Iijima et al., 2002; Van Keymeulen
et al., 2006; Nishio et al., 2007; Heit et al., 2008).
Alterations in leukocyte polarity could therefore provide
an alternative means of disrupting PTEN function to
contribute to leukemogenesis.
Notch
Notch signaling regulates a wide variety of cellular
processes, including stem cell maintenance and cell-fate
decisions through the modification of differentiation,
proliferation and apoptosis (Ehebauer et al., 2006), and
this is particularly well studied in the hematopoietic
system (Rothenberg et al., 2008). Notch signaling has a
key function in the development of leukemia, particularly in T-ALL (Grabher et al., 2006). Constitutive
expression of an active signaling cleavage product of
Notch under the TCRb promoter/enhancer is found in
human T-ALL patients with a rare (7;9) (q34;q34.3)
translocation (Ellisen et al., 1991). More convincingly,
mutations in the PEST domain of Notch, which lead to
increased Notch signaling, are found in over 50% of all
pediatric T-ALL cases (Weng et al., 2004). These
findings are also supported by a variety of animal
models with deregulated Notch signaling that develop
leukemia (Grabher et al., 2006). The Notch signaling
pathway is not classically considered to regulate
polarity, however, Notch-1 signaling can negatively
regulate the expression of PTEN (Palomero et al.,
2007) and thus Notch-1 signaling might also have an
important function in migration responses to chemokine
signals. Additionally, signaling through the Notch
pathway can be asymmetrically distributed by localization either of one of its ligands, or of the regulator of
Notch, Numb (see Notch and ACD below). polarization
of mature T cells in response to antigen presentation is
accompanied by polarization of Numb (Anderson et al.,
2005), so loss of polarity might represent an additional
means of deregulating Notch signaling in thymocytes to
trigger T-ALL. Further support for a possible involvement of polarity in Notch-mediated tumorigenesis
comes from a new mouse model of T-ALL, in which
the constitutive activation of the T-cell polarity regulator, Rap1, leads to Notch activation and T-cell
leukemia (Wang et al., 2008).
ACD in leukocytes
One aspect of cell polarity that can have profound
consequences during development is ACD (see review
by Januschke and Gonzalez, 2008). ACD involves the
induction and maintenance of polarity during cell
Oncogene
Polarity and asymmetric cell division in leukemia
ED Hawkins and SM Russell
7008
division, resulting in the production of two daughter
cells with different molecular composition (reviewed by
Betschinger and Knoblich, 2004; Morrison and Kimble,
2006). The asymmetrically localized proteins often
include determinants of cell fate, so ACD can orchestrate the differentiation of progeny in a highly regulated
manner (Figure 3). ACD regulates development from
the first division of the fertilized zygote in many
organisms, and also has a function in diverse developmental processes, including neuroblast differentiation
and skin development. Depending on the cell type and
physiological context, polarity during ACD can be
triggered by extrinsic cues such as neighboring cells or a
molecular marker of the site of fertilization.
ACD can also regulate proliferation potential, and an
important function of ACD is the maintenance of selfrenewal capacity in stem cells. For instance, division of
Drosophila neuroblasts involves the production of one
daughter that can proliferate to form the differentiated
neurons (the ganglion mother cell), and a second
daughter that is a replica of the parent neuroblast (see
Januschke
and
Gonzalez,
2008).
Similarly,
Drosophila germline stem cells rely on ACD for
determination of self-renewal and differentiation potential. The Drosophila germline stem cell divides to
generate one daughter that remains tightly associated
with the niche and retains stem cell-like properties, and
another that initiates a differentiation program (Yamashita et al., 2003; Xie and Li, 2007). The orientation of
these divisions controls the molecular identity of
daughter cells and their access to extrinsic signals that
regulate stem cell identity. This appears to be a general
pattern in ACD, one daughter follows a programmed
pattern of proliferation and differentiation, and the
Proliferation
Finite proliferative potential
Quiescence
Protection from apoptosis
Prevention of differentiation
Capacity for self-renewal
Figure 3 Asymmetric cell division (ACD) involves asymmetric
distribution of multiple biological properties into each of the
daughter cells. Each colored circle represents a different biological
property as shown, and might be regulated by a number of
asymmetrically distributed molecules (including protein and RNA,
probably microRNA). Subtle differences in the distribution of
molecules could alter one or more of the biological properties
illustrated, while still enabling ACD.
Oncogene
self-renewing daughter inherits a propensity for quiescence along with the capacity for longevity. Appropriately therefore, ACD seems to have a function in
almost every well-studied system involving stem cells or
stem cell-like components (Morrison and Kimble, 2006).
There is considerable interest in determining whether
the self-renewal and differentiation of HSCs might also
involve ACD. The comparatively slow progress in our
understanding of this process reflects the difficulties in
studying ACD in a motile cell without readily apparent
tissue organization. The importance of the niche in the
maintenance of HSCs has been the subject of much
research in recent years, and most likely provides good
clues as to where ACD of HSC might occur and how
polarity during ACD might be regulated (Kiel and
Morrison, 2008). For instance, HSCs are often seen
in close proximity with osteoblasts in the bone marrow,
or endothelial cells from adjacent blood vessels in the
bone marrow or sinusoids in extramedullary sites, and
these might directly (through cell–cell interaction)
or indirectly (through chemokine gradients) regulate
polarity and ACD (Figure 4b).
Some studies, operating on the assumption that ACD
in HSC might be regulated by intrinsic polarity that
could be mimicked in vitro, looked for asymmetry in the
daughters of in vitro cultured HSCs (Takano et al., 2004;
Giebel et al., 2006; Beckmann et al., 2007). Identification
of asymmetry under these conditions provided encouraging suggestions that ACD can occur in HSC, but the
possibility that this asymmetry might occur through
random differences in protein segregation could not be
ruled out. Wu et al. (2007b) recently provided two
important advances to these studies. First, by showing
that asymmetry could be influenced by culture with
different stromal cells, they provided the first evidence
that ACD of HSC could be determined by extrinsic
events. Second, using a green fluorescent protein-based
reporter for Notch signaling, they demonstrated that
ACD in HSC created signaling differences that were
compatible with self-renewal of one daughter cell.
Although the concept that ACD might also regulate
diversity and fate determination of more differentiated
lymphocytes was raised decades ago (Sainte-Marie and
Leblond, 1965; Metcalf and Wiadrowski, 1966), it has
come to prominence only recently with a study by Steve
Reiner and colleagues (Chang et al., 2007). In this study,
CD8 þ T cells were extracted from mice at the time of
first division following Listeria infection, and mitotic
lymphocytes inspected by microscopy to find clear
evidence of asymmetry. Importantly, both Numb and
the polarity regulators Scribble and aPKC were
polarized in the dividing cells, indicating that the
previously defined mechanisms of ACD were most
likely conserved in lymphocytes. The asymmetric
localization of surface molecules in the mitotic cells
correlated with their bipolar distribution in the daughters. The daughters were sorted and subjected to
functional analysis, which indicated that the putative
distal daughter, but not the putative proximal daughter,
was capable of generating a memory response. These
exciting data not only demonstrate that ACD can occur
Polarity and asymmetric cell division in leukemia
ED Hawkins and SM Russell
7009
a
Thymus
c
Vascular tissue
d
Peripheral lymphoid
organ
?
? ?
b
Bone Marrow
-
Differentiation
Figure 4 Different forms of polarity might regulate asymmetric cell division (ACD) in normal leukocytes and leukemic cells.
(a) Interactions with stromal factors in the thymus, such as Notch-1 ligands on thymic epithelial cells, might regulate an axis for ACD.
Polarized interactions such as this may have an important function in asymmetric distribution of intracellular fate determinants that
dictate precursor cell differentiation and self-renewal, or might enable preferential contact of the stromal cell with the distal daughter
cell after division, regulating differential fate determination. (b) In the bone marrow, hematopoietic stem cells (HSCs) and leukemic
cells might interact with osteoblasts and endothelial cells to maintain self-renewal capacity (Morrison and Spradling, 2008). (c) In the
periphery, homotypic interactions might provide an axis that has the potential to enable ACD. (d) In lymph nodes, antigen
presentation causes ligands and intracellular cell determinants such as CD8, LFA-1, PKCz and Numb to be distributed
asymmetrically. Division along an axis of polarity (dashed line) gives rise to two daughter cells with different phenotypes that undergo
subsequent proliferation to generate memory and effector T cells.
in mature lymphocytes but also strongly suggest that
ACD of lymphocytes regulates cell lineage determination (Figure 4d) (Chang et al., 2007).
These experiments pave the way for future studies
to determine whether ACD also occurs in other
lymphocytes, and in T cells that are polarized under
different circumstances (for instance, during responses
to chemokines; Figure 4a interaction with other cells
such as thymic epithelial cells, or homotypic adhesion;
Figure 4c). Indeed, the lineage developmental program
for many hematopoietic cells involves waves of proliferation that include at least partial self-renewal (for
instance, during thymocyte development, or expansion
of myeloid and lympoid precursors). In each case, ACD
might have a function in regulating the balance between
expansion of differentiating cells, and maintenance of a
precursor population.
How might ACD impact on leukemia?
Not surprisingly, key constituents in the regulation of
ACD are the polarity regulators, including those
designated as tumor suppressors (Gonzalez, 2007;
Coumailleau and Gonzalez-Gaitan, 2008; Knoblich,
2008; Januschke and Gonzalez, 2008). The Par3 complex has been implicated in ACD in a number of cell
systems, originally with a role in the fertilized Caenorhabditis elegans oocyte (Kemphues et al., 1988; Aranda
et al., 2008). In Drosophila neuroblasts, Par3 (bazooka)
cooperates with Par6 and aPKC to mediate the
localization of cell-fate determinants to the opposite
pole of the cell (Knoblich, 2008). All three members of
the Scribble complex also have an essential function in
ACD (Albertson and Doe, 2003) (reviewed in Humbert
et al., 2008). Most evidence relates to Lgl, which is
essential for the asymmetric distribution of cell-fate
determinants in Drosophila neuroblasts and sensory
organ precursors (Peng et al., 2000; Langevin et al.,
2005; Roegiers et al., 2005; Betschinger et al., 2006; Lee
et al., 2006b; Knoblich, 2008). Dlg coordinates orientation of the mitotic spindle with polarization of cell-fate
determinants (Siegrist and Doe, 2005), and is involved
with Lgl in neuroblast asymmetry during ACD (Ohshiro
et al., 2000). These observations have led to the concept
that the tumor suppressing activities of Scribble, Dlg
and Lgl might, at least in part, involve their role in ACD
(Gonzalez, 2007; Coumailleau and Gonzalez-Gaitan,
2008).
The notion that ACD allows for the segregation of
proliferative and self-renewal capacity into different
daughters is important for current concepts of oncogenesis (Figure 5). There is a growing thought that cancer
might arise from stem cells in some instances (Bonnet
and Dick, 1997; Cobaleda et al., 2000; Reya et al., 2001;
Castor et al., 2005; Buzzeo et al., 2007). Cancers might
arise following the aberrant distribution of cell-fate
determinants during the asymmetric division of a stem
cell. Instead of generating one daughter that can selfrenew and one that proliferates rapidly but has a limited
lifespan (Figure 5a), this might generate a cell that has
both self-renewal properties and the capacity to
proliferate rapidly (Figure 5b). Studies in Drosophila
have provided strong proof for this hypothesis, and
there is now a growing body of evidence in solid
malignancies to suggest that disruptions in ACD can
Oncogene
Polarity and asymmetric cell division in leukemia
ED Hawkins and SM Russell
7010
Figure 5 Many shades of gray in how asymmetric cell division (ACD) might lead to leukemia. (a) The classic picture of ACD relates
to the idea that two daughter cells differentially adopt the properties of self-renewal (with quiescence, white cells) or some degree of
differentiation (combined with rapid proliferation and a finite number of divisions, black cells). (b) Prevention of ACD might, in
certain circumstances, lead to coinheritance of both self-renewal and proliferative capacity (gray), perhaps creating a population of
cells that have increased propensity to become leukemic. (c) Alternatively, cancer might arise when ACD is slightly altered, for instance
to subtly change either the proliferation rate of the ‘self-renewing cells (that is, white cells become light gray) (i), or in the proliferative
potential of the ‘non-self-renewing cells’ (that is, black cells become dark gray) (ii). Note that the pale gray cell in (i) not only has the
potential to initiate a tumor but by its self-renewing properties would also have the capacity to act as a cancer stem cell.
lead to hyperproliferation and cancer (Gonzalez, 2007;
Coumailleau and Gonzalez-Gaitan, 2008). One such
example relates to the phenotype of mice in which the
Oncogene
Scribble complex protein, Lgl, was deleted (Klezovitch
et al., 2004). Loss of Lgl disrupts ACD of neuronal
precursors, which results in the expression of Numb in
Polarity and asymmetric cell division in leukemia
ED Hawkins and SM Russell
7011
each daughter, and the consequent overproliferation of
the self-renewing cells, reminiscent of the proliferative
disorder primitive neuroectodermal tumors) (Klezovitch
et al., 2004).
The concept that cancers can arise from stem cells is
particularly well supported for leukemia, and would
therefore involve the subversion of HSC. Only slight
enhancements of self-renewal potential in the proliferating population (Figure 5ci), or conversely, of proliferative capacity in the differentiated population (Figure
5cii), could lead to lymphoproliferation that has the
potential to predispose to the secondary transforming
mutations commonly found in models of leukemia.
With this model of ACD in mind, we can draw parallels
with different stages of leukemogenesis. Accumulation
of differentiated cells and ongoing division of stem cells
as shown in Figure 5ci is similar to chronic phase in
CML, and to the survival and proliferation of myeloblasts in AML, whereas Figure 5cii may reflect the CML
blast crisis, and myeloproliferative diseases that precede
acute leukemia (Nimer, 2008). This process might not
just apply to HSC, but hyperproliferation at any stage of
hematopoietic development could predispose to leukemia, and could perhaps also arise by disruptions in
ACD.
Indeed, recent studies showed that the conditional
deletion of Dlg1 can negatively regulate proliferation of
T cells under some circumstances (Stephenson et al.,
2007). Many of the proteins implicated in leukemia
might therefore exert at least some of their effects by
deregulating ACD, or by having altered function if they
are not distributed appropriately during ACD of HSC.
In support of this notion, expression of the NUP98HOXA9 fusion protein associated with AML and CML
altered the pattern of asymmetric versus symmetric
divisions in HSC cultured with stromal cells (Wu et al.,
2007b). Here, we will discuss how ACD might impact on
the three leukemogenic pathways described above.
Notch in ACD
Exposure to Notch ligands prevents differentiation of
HSCs and causes them to maintain a stem cell-like
character (Jones et al., 1998; Varnum-Finney et al.,
1998). Furthermore, components of the Notch signaling
pathway are consistently asymmetric in the daughters of
an ACD, and this is key for determining their
differential cell fate (Knoblich, 2008). In Drosophila,
differential Notch activation in the daughters of an
asymmetric division of a homogenous neuronal precursor population regulates the development of two
distinct cell lineages (Lee et al., 2006a; Bowman et al.,
2008). Given the important role of Notch in regulating
self-renewal potential, and differentiation, it is not hard
to imagine that control of Notch signaling by ACD is an
essential component of tumor suppression. Negative
regulation of Notch signaling by the asymmetrically
distributed protein Numb can influence apoptosis and
differentiation during sensory organ development
(Orgogozo et al., 2002). Furthermore, the neuroblasts
of a Drosophila mutant that expresses functional but
unpolarized Numb displays an identical phenotype to
those in Drosophila lacking Numb expression, providing
even stronger evidence that the asymmetry of Numb
dictates differential fate of the daughters (Bhalerao
et al., 2005). As described above, the observation that
loss of Lgl gives rise to a primitive neuroectodermal
tumor-like disorder due to mislocalization of Numb in
ACD (Klezovitch et al., 2004) supports this notion. The
recent observations by Tanishtha Reya and colleagues
that Numb can be asymmetric in dividing HSC, and that
this correlates with differential Notch activity in the
daughter cell, provide for the exciting possibility that
disruptions in ACD of HSC might predispose to
leukemia by affecting Notch signaling (Wu et al.,
2007b; Congdon and Reya, 2008). The role of Dlg,
Scribble and Lgl in the regulation of Numb localization
during ACD (Knoblich, 2008) further suggests that
alterations in their function might lead to leukemia by
disrupting ACD and therefore self-renewal of HSC.
Wnt in ACD
Besides the role for Wnt in regulating polarity of a nondividing cell, the Wnt signaling pathway might also
influence leukemia through ACD. A role for the Wnt
pathway in ACD is highly conserved, and has been
observed in C. elegans, sea anemone and zebrafish
(Wikramanayake et al., 2003; Gong et al., 2004;
Mizumoto and Sawa, 2007a, b; Hardin and King,
2008). There is also growing evidence that Wnt signaling
has an important function in self-renewal of hematopoietic progenitors and stem cells. The ligands for the
Wnt pathway (Wnt proteins) are produced not only by
HSC but also by other constituents of the HSC
microenvironment (Rattis et al., 2004). In vitro addition
of Wnt, in addition to stem cell factor, inhibits
differentiation and promotes growth of HSC.
These observations together suggest the possibility
that Wnt signaling might regulate ACD to affect selfrenewal of HSC, and therefore that the Wnt signaling
defects associated with leukemia might involve disruptions in ACD. Enforced expression of Wnt in granulocyte macrophage progenitors has been demonstrated to
give them ‘stem cell-like’ self-renewal potential, and Wnt
signaling is found to be upregulated in these progenitors
in CML patients. Disruption of b-catenin in BCR-Abl
animal models of leukemia reduces the ability of HSC to
self-renew both in vivo and in vitro, significantly delays
the development of disease and shifts the disease from a
CML phenotype to an ALL phenotype (Zhao et al.,
2007).
PTEN in ACD
A role for PTEN in ACD has not been exhaustively
studied, but is suggested by observations that
PtdIns(3,4,5)P3 regulates spindle orientation in the
HeLa cell line (Toyoshima et al., 2007). PtdIns(3,4,5)P3
is maintained at both poles of a T cell on activation
(Costello et al., 2002), and can stabilize leukocyte
polarity (Wang et al., 2002), suggesting that it would
have the capacity to regulate ACD in leukocytes.
Oncogene
Polarity and asymmetric cell division in leukemia
ED Hawkins and SM Russell
7012
Recently, animal studies have shed light on the function
of PTEN in the maintenance of normal HSC function.
In HSC, PTEN promotes quiescence and prevents entry
into the cell cycle. Thus, HSC from mice lacking PTEN
initially multiply rapidly; however, they are depleted
within weeks, and display diminished self-renewal
capacity in serial transplantation assays (Yilmaz et al.,
2006; Zhang et al., 2006). Furthermore, these mice
develop a brief myeloproliferative disorder followed by
acute leukemia (Yilmaz et al., 2006; Zhang et al., 2006).
As a result of PTEN inactivation, a population of
cKitmid, CD3 þ ve cells accumulate that are highly
enriched for leukemia-initiating cells, develop further
oncogenic mutations and are capable of disease transplantation to irradiated recipients (Guo et al., 2008).
These leukemia-initiating cells were found to migrate
out of the bone marrow, colonize peripheral lymphoid
organs and initiate the development of leukemic-like
disease. LICs, which were capable of transferring
disease, were also found in these peripheral organs
(Guo et al., 2008). Observations made using this animal
model make two important points. First, they support
the possibility that deregulation of ACD, by affecting
the balance between self-renewal and proliferation, can
lead to a population of cells with increased leukemic
potential. Second, they also provide some support for
the notion that polarity cues outside the bone marrow
can also allow for self-renewal, perhaps by coordinating
ACD. Thus, either PTEN might regulate ACD, or ACD
might impact on PTEN function, and disruptions in this
process might lead to leukemogenesis.
Leukemic stem cells
Just as a disruption in ACD can be considered an
initiating event in the conversion of a stem cell to a
cancer cell, the other side of the coin might be an
adoption of ACD to enable the maintenance of cancer
stem cells. The notion of a cancer stem cell is currently
hotly debated, and the term means different things to
different people. For the purposes of this review, we
define a cancer stem cell as a cell within the heterogeneous population of cancer cells that is relatively
quiescent, but has self-renewal properties that give it a
capacity to regenerate the tumor bulk. This entity might,
or might not be related to the putative ‘cancer-initiating
cell’ described above that is proposed to arise from stem
cells. Cancer stem cells, or leukemic stem cells, are of
interest to oncologists because these might be the cells
that can resist therapeutic regimens as a result of their
quiescence. Cancer stem cells have been discussed for
decades and there is considerable controversy related to
this subject. However, confidence is growing that they
have an important function in a number of malignancies, particularly in leukemia (Li and Neaves, 2006;
Savona and Talpaz, 2008).
As with normal stem cells, by definition a cell that can
both self-renew and reconstitute the cancer bulk must be
able to produce two daughters with different fates. The
Oncogene
precedents described above indicate that this process
might well be orchestrated by ACD. Furthermore, the
idea that ACD can facilitate self-renewal by packaging
of key determinants leads to the extreme (almost
heretical) notion that perhaps any cell can generate
daughters with different capacities for self-renewal and
proliferation. Therefore, a cancer stem cell might arise
from a more differentiated cancer cell, and might not
necessarily be directly derived from the cancer-initiating
cell (Figure 6a). Thus, a major determinant of whether
the daughters will adopt appropriate homeostasis or
uncontrolled proliferation and cancer might, in addition
to the identity of the parent cell, involve the ability of
that parent cell to undergo ACD, and to asymmetrically
package the molecular determinants of proliferation and
self-renewal. That ACD might provide the capacity to
regenerate self-renewal capacity from a more differentiated cell is compatible with the increasing identification of subsets of ‘non-stem cells’ that under certain
conditions can be induced to adopt stem cell-like
properties, and with the growing notion of plasticity
among stem cell and more differentiated progenitors
(Okita et al., 2007; Wernig et al., 2007). Indeed, it has
been proposed that the clones of myeloproliferative
disorders might not only utilize the stem cell niche to
orchestrate ACD but also might outcompete normal
HSCs for that niche (Nimer, 2008).
How might ACD be orchestrated in leukemic cells
to generate or maintain a self-renewing population?
Again, understanding how and where ACD might be
controlled in the cancer stem cell population is essential
for elucidating the process. Leukemic stem cells might
adopt mechanisms for enabling ACD that have nothing
to do with their origin, for instance utilizing the polarity
orchestrated by HTLV-1 in the case of ATLL (the
virological synapse; Figure 2b) (Mortreux et al., 2003;
Yoshida et al., 2008) or perhaps other forms of
homotypic adhesion (Figure 4c). This would mean that
ACD could occur wherever two leukemic cells interact,
or even in the interaction between an infected and a noninfected cell. Alternatively, a leukemic stem cell might
adopt the polarity cues of its precursor to mediate ACD.
If the leukemic cell arises, for instance, from a
thymocyte and the stem cells continue to reside in the
thymus, then interactions with thymic epithelial cells
might control ACD (Xue et al., 2008). If a leukemic cell
adopts the properties of a HSC, then it might utilize the
HSC niche to enable ACD, and there is growing support
for this concept. For instance, human AML cells
transplanted into immunodeficient mice also engraft in
the endosteal region of the bone marrow, and the
putative leukemic stem cell population engraft better
than the leukemic cells that do not express stem cell
markers (Ishikawa et al., 2007). This niche would
provide an ideal environment both to orchestrate
ACD of leukemic stem cells and to mediate
distinct responses of the daughter cells (Figure 4b).
Polarity and asymmetric cell division in leukemia
ED Hawkins and SM Russell
7013
Figure 6 Even more shades of gray for asymmetric cell division (ACD) in the cancer stem cell hypothesis. (a) The plasticity of
leukemic cells and the fact that even normal cells are now thought to have the capacity to regain some stem cell-like (and therefore selfrenewal) capacity indicate that cancer stem cells might arise from rapidly proliferating leukemic cells. ACD at any stage in leukemic
progression might therefore enable the generation of a population of leukemic cells with a slightly altered balance of self-renewal and
proliferative properties. The properties of their daughters in turn might depend in part on properties inherited from the parent cell,
and in part on whether and how ACD is enabled in the parent. (b) The combined effects of both genetic and epigenetic inheritance, and
differential segregation of molecules during ACD, could lead to a wide variation of cells within the leukemic population, with
canonical properties of stem cells, rapid proliferation or intermediate characteristics. The properties of their progeny might again
depend in part on the genetic and epigenetics of the parent, and in part on whether (and how) they undergo ACD.
Furthermore, structure and development of the niches
themselves are also capable of being regulated, and the
presence of abnormally localized immature precursors
has been suggested to be a useful prognostic indicator in
the diagnosis of myelodysplastic syndromes and chronic
myelomonocytic leukemia (Verburgh et al., 2003; Ngo
et al., 2008). Therefore, we must also consider the
possibility that manipulation and alterations of the
niche itself, and not resident stem cells, might be a
means to deregulate self-renewal and differentiation
(Sneddon and Werb, 2007). The next step is to
demonstrate ACD in such an environment, and to
begin exploring how disruption of ACD in the niche
might impact on leukemic stem cell maintenance.
With regard to the concept of leukemic stem cells, one
could then imagine a scenario in which the control of
polarity and ACD in leukemic cells might regulate
a capacity to flip between proliferative and self-renewal
potential from one generation to another (Figure 6b).
Depending on the requirements for triggering ACD in a
leukemia cell, it is possible that the occasional cell might
make its way to, for instance, the endosteal niche of the
bone marrow, or a particular region of the lymph node.
If this environment is conducive to ACD, the cell could
then generate a rapidly proliferating daughter as well as
a self-renewing daughter (a leukemic stem cell). The
leukemic stem cell might then stay in the niche and
continue a slow but steady production of proliferating
progeny and self-renewed daughters, but at any stage
might leave the niche and consequently lose its stem celllike self-renewing properties. A recent study that
provides some support for the notion of context-specific
regulation of cancer stem cell self-renewal demonstrates
that the direct injection of human ALL cells into the
femur of immunodeficient mice allows for reestablishment of ALL irrespective of whether the injected cells
are purified for stem cell-like immunophenotypes
(le Viseur et al., 2008). This study suggests that cancer
cells can adopt the stem cell-like properties of selfrenewal and multipotency when provided with an
appropriate niche, despite not expressing the classic
stem cell markers.
Perhaps then, as well as looking for markers with
which to prospectively identify and isolate leukemic
stem cells, and determining how these behave when
reintroduced into animals, we should also look at where
and how ACD is facilitated, and whether this process
corresponds to the production of self-renewing, relatively quiescent daughters. Fortunately, much of the
work on cancer stem cells is now focused on identifying
the niches that allow for self-renewal (Sneddon and
Werb, 2007), and this will enable assessment of how
polarity and ACD might regulate the generation or
maintenance of cancer stem cells.
How will we conclusively determine whether polarity
and ACD have important functions in leukemia? The
Oncogene
Polarity and asymmetric cell division in leukemia
ED Hawkins and SM Russell
7014
growing number of mice deficient in polarity proteins
will enable assessment of the role of each in established
murine models of leukemia. The rapidly improving
ability to screen leukemias systematically for genomewide alterations in expression, SNPS and epigenetic
modifications will allow for assessment of the involvement of each polarity gene in the context of other
mutations. One important consideration is that as ACD
by definition encompasses the classically considered role
of proliferation, apoptosis, trafficking and so on, we will
not easily dissect a function for ACD by standard
molecular approaches. However, defining where and
how ACD might occur will enable some more sophisticated approaches, particularly as means to disrupt
ACD are rapidly being elucidated in other systems. As
an example, overexpression of a portion of b-adrenergic
receptor kinase can disrupt ACD (Sanada and Tsai,
2005). Conditional expression of such a molecule at the
time and place of ACD would enable the determination
of whether the asymmetric distribution of molecules at
the time of division is crucial for leukemic onset or
progression. To perform the molecular dissections that
enable clear models for the function of ACD in leukemia
and leukemia stem cells, a number of questions must be
answered first:
Can HSC, differentiated lymphocytes or leukemic
cells be induced to undergo ACD given the appropriate cues and environment, and what are these cues?
Can this lead to daughter cells with increased capacity
for self-renewal, and are HSCs better able to selfrenew because they are more likely to undergo ACD?
If so, is it their environment or intrinsic, stem cellspecific factors that influence their propensity for
ACD?
What are the factors that dictate cell fate in the
daughters of lymphocytes, HSCs or leukemic cells
undergoing ACD?
Can ACD of a differentiated cell create a daughter
with self-renewal capacity?
Are there similarities or cooperation between asymmetrically distributed proteins and the proteins
implicated in leukemogenesis or prognosis?
Do alterations in the distribution of proteins during
ACD of lymphocytes or HSC predispose to leukemia?
Does ACD allow for the generation and/or maintenance of a subset of leukemic cells with the capacity
for quiescence and self-renewal?
Conclusion
Evidence is now very strong that polarity is likely to
have an important function in leukemogenesis, and that
Dlg, Scribble and Lgl might act as tumor suppressors in
lymphocytes as well as in epithelial cells. Of particular
interest is the possibility that ACD has key functions in
leukemia. This could occur at two levels. First, ACD
might be important in preventing leukemia, for instance
by segregating self-renewal and proliferative potential
into the two daughter cells of a HSC. Second, ACD
might enable the generation and maintenance of
leukemic stem cells.
Acknowledgements
We thank David Ritchie, Paul Neeson, Grant MacArthur and
Helena Richardson for insightful comments on the paper, and
members of the Russell lab for helpful discussion.
References
Affolter M, Weijer CJ. (2005). Signaling to cytoskeletal dynamics
during chemotaxis. Dev Cell 9: 19–34.
Aggerholm A, Gronbaek K, Guldberg P, Hokland P. (2000).
Mutational analysis of the tumour suppressor gene MMAC1/PTEN
in malignant myeloid disorders. Eur J Haematol 65: 109–113.
Albertson R, Doe CQ. (2003). Dlg, Scrib and Lgl regulate neuroblast
cell size and mitotic spindle asymmetry. Nat Cell Biol 5: 166–170.
Anderson AC, Kitchens EA, Chan SW, St Hill C, Jan YN, Zhong W
et al. (2005). The Notch regulator Numb links the Notch and TCR
signaling pathways. J Immunol 174: 890–897.
Aranda V, Nolan ME, Muthuswamy SK. (2008). Par complex in
cancer: a regulator of normal cell polarity joins the dark side.
Oncogene 27: 6878–6887.
Barnard AL, Igakura T, Tanaka Y, Taylor GP, Bangham CR. (2005).
Engagement of specific T-cell surface molecules regulates
cytoskeletal polarization in HTLV-1-infected lymphocytes. Blood
106: 988–995.
Beckmann J, Scheitza S, Wernet P, Fischer JC, Giebel B. (2007).
Asymmetric cell division within the human hematopoietic stem and
progenitor cell compartment: identification of asymmetrically
segregating proteins. Blood 109: 5494–5501.
Betschinger J, Knoblich JA. (2004). Dare to be different: asymmetric
cell division in Drosophila, C. elegans and vertebrates. Curr Biol 14:
R674–R685.
Betschinger J, Mechtler K, Knoblich JA. (2006). Asymmetric
segregation of the tumor suppressor brat regulates self-renewal in
Drosophila neural stem cells. Cell 124: 1241–1253.
Oncogene
Bhalerao S, Berdnik D, Torok T, Knoblich JA. (2005). Localizationdependent and -independent roles of numb contribute to cell-fate
specification in Drosophila. Curr Biol 15: 1583–1590.
Bilder D. (2004). Epithelial polarity and proliferation control: links
from the Drosophila neoplastic tumor suppressors. Genes Dev 18:
1909–1925.
Blot V, Delamarre L, Perugi F, Pham D, Benichou S, Benarous R et al.
(2004). Human Dlg protein binds to the envelope glycoproteins of
human T-cell leukemia virus type 1 and regulates envelope mediated
cell–cell fusion in T lymphocytes. J Cell Sci 117: 3983–3993.
Bonnet D, Dick JE. (1997). Human acute myeloid leukemia is
organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3: 730–737.
Bowman SK, Rolland V, Betschinger J, Kinsey KA, Emery G,
Knoblich JA. (2008). The tumor suppressors Brat and Numb
regulate transit-amplifying neuroblast lineages in Drosophila. Dev
Cell 14: 535–546.
Bromley SK, Peterson DA, Gunn MD, Dustin ML. (2000). Cutting
edge: hierarchy of chemokine receptor and TCR signals regulating T
cell migration and proliferation. J Immunol 165: 15–19.
Buzzeo MP, Scott EW, Cogle CR. (2007). The hunt for cancerinitiating cells: a history stemming from leukemia. Leukemia 21:
1619–1627.
Castor A, Nilsson L, Astrand-Grundstrom I, Buitenhuis M, Ramirez
C, Anderson K et al. (2005). Distinct patterns of hematopoietic
stem cell involvement in acute lymphoblastic leukemia. Nat Med 11:
630–637.
Polarity and asymmetric cell division in leukemia
ED Hawkins and SM Russell
7015
Chang JT, Palanivel VR, Kinjyo I, Schambach F, Intlekofer AM,
Banerjee A et al. (2007). Asymmetric T lymphocyte division in the
initiation of adaptive immune responses. Science 315: 1687–1691.
Cobaleda C, Gutierrez-Cianca N, Perez-Losada J, Flores T,
Garcia-Sanz R, Gonzalez M et al. (2000). A primitive hematopoietic
cell is the target for the leukemic transformation in human
Philadelphia-positive acute lymphoblastic leukemia. Blood 95:
1007–1013.
Coluccia AM, Vacca A, Dunach M, Mologni L, Redaelli S, Bustos VH
et al. (2007). Bcr-Abl stabilizes beta-catenin in chronic
myeloid leukemia through its tyrosine phosphorylation. EMBO J
26: 1456–1466.
Comer FI, Parent CA. (2007). Phosphoinositides specify polarity
during epithelial organ development. Cell 128: 239–240.
Congdon KL, Reya T. (2008). Divide and conquer: how asymmetric
division shapes cell fate in the hematopoietic system. Curr Opin
Immunol 20: 302–307.
Costello PS, Gallagher M, Cantrell DA. (2002). Sustained and
dynamic inositol lipid metabolism inside and outside the immunological synapse. Nat Immunol 3: 1082–1089.
Coumailleau F, Gonzalez-Gaitan M. (2008). From endocytosis to
tumors through asymmetric cell division of stem cells. Curr Opin
Cell Biol 20: 462–469.
Cully M, You H, Levine AJ, Mak TW. (2006). Beyond PTEN
mutations: the PI3K pathway as an integrator of multiple inputs
during tumorigenesis. Nat Rev Cancer 6: 184–192.
Dahia PL, Aguiar RC, Alberta J, Kum JB, Caron S, Sill H et al.
(1999). PTEN is inversely correlated with the cell survival factor
Akt/PKB and is inactivated via multiple mechanisms in haematological malignancies. Hum Mol Genet 8: 185–193.
Dollar GL, Weber U, Mlodzik M, Sokol SY. (2005). Regulation of
Lethal giant larvae by Dishevelled. Nature 437: 1376–1380.
Dustin ML. (2002). Regulation of T cell migration through formation
of immunological synapses: the stop signal hypothesis. Adv Exp
Med Biol 512: 191–201.
Ehebauer M, Hayward P, Arias AM. (2006). Notch, a universal arbiter
of cell fate decisions. Science 314: 1414–1415.
Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD
et al. (1991). TAN-1, the human homolog of the Drosophila notch
gene, is broken by chromosomal translocations in T lymphoblastic
neoplasms. Cell 66: 649–661.
Etienne-Manneville S. (2008). Polarity proteins in migration and
invasion. Oncogene 27: 6970–6980.
Etienne-Manneville S, Hall A. (2003). Cdc42 regulates GSK-3beta and
adenomatous polyposis coli to control cell polarity. Nature 421:
753–756.
Etienne-Manneville S, Manneville JB, Nicholls S, Ferenczi MA, Hall
A. (2005). Cdc42 and Par6-PKCzeta regulate the spatially localized
association of Dlg1 and APC to control cell polarization. J Cell Biol
170: 895–901.
Fukuda R, Hayashi A, Utsunomiya A, Nukada Y, Fukui R,
Itoh K et al. (2005). Alteration of phosphatidylinositol 3-kinase
cascade in the multilobulated nuclear formation of adult T
cell leukemia/lymphoma (ATLL). Proc Natl Acad Sci USA 102:
15213–15218.
Gerard A, Mertens AE, van der Kammen RA, Collard JG. (2007). The
Par polarity complex regulates Rap1- and chemokine-induced T cell
polarization. J Cell Biol 176: 863–875.
Giagulli C, Scarpini E, Ottoboni L, Narumiya S, Butcher EC,
Constantin G et al. (2004). RhoA and zeta PKC control distinct
modalities of LFA-1 activation by chemokines: critical role of
LFA-1 affinity triggering in lymphocyte in vivo homing. Immunity
20: 25–35.
Giebel B, Zhang T, Beckmann J, Spanholtz J, Wernet P, Ho AD et al.
(2006). Primitive human hematopoietic cells give rise to differentially specified daughter cells upon their initial cell division. Blood
107: 2146–2152.
Gong Y, Mo C, Fraser SE. (2004). Planar cell polarity signalling
controls cell division orientation during zebrafish gastrulation.
Nature 430: 689–693.
Gonzalez C. (2007). Spindle orientation, asymmetric division and tumour
suppression in Drosophila stem cells. Nat Rev Genet 8: 462–472.
Grabher C, von Boehmer H, Look AT. (2006). Notch 1 activation in
the molecular pathogenesis of T-cell acute lymphoblastic leukaemia.
Nat Rev Cancer 6: 347–359.
Guo W, Lasky JL, Chang CJ, Mosessian S, Lewis X, Xiao Y et al.
(2008). Multi-genetic events collaboratively contribute to Pten-null
leukaemia stem-cell formation. Nature 453: 529–533.
Guo Z, Dose M, Kovalovsky D, Chang R, O’Neil J, Look AT et al.
(2007). Beta-catenin stabilization stalls the transition from doublepositive to single-positive stage and predisposes thymocytes to
malignant transformation. Blood 109: 5463–5472.
Hardin J, King RS. (2008). The Long and the short of Wnt signaling in
C. elegans. Curr Opin Genet Dev (doi:10.1016/j.gde.2008.06.006).
Heit B, Robbins SM, Downey CM, Guan Z, Colarusso P, Miller BJ
et al. (2008). PTEN functions to ‘prioritize’ chemotactic cues
and prevent ‘distraction’ in migrating neutrophils. Nat Immunol 9:
743–752.
Hezel AF, Bardeesy N. (2008). LKB1; limking cell structure and tumor
suppression. Oncogene 27: 6908–6919.
Huber MA, Kraut N, Beug H. (2005). Molecular requirements for
epithelial–mesenchymal transition during tumor progression. Curr
Opin Cell Biol 17: 548–558.
Humbert P, Russell S, Richardson H. (2003). Dlg, Scribble and Lgl in
cell polarity, cell proliferation and cancer. Bioessays 25: 542–553.
Humbert PO, Dow LE, Russell SM. (2006). The Scribble and Par
complexes in polarity and migration: friends or foes? Trends Cell
Biol 16: 622–630.
Humbert PO, Grzeschik NA, Brumby AM, Galea R, Elsum I,
Richardson HE. (2008). Control of tumourigenesis by the Scribble/
Dlg/Lgl polarity module. Oncogene 27: 6888–6907.
Igakura T, Stinchcombe JC, Goon PK, Taylor GP, Weber JN,
Griffiths GM et al. (2003). Spread of HTLV-I between lymphocytes
by virus-induced polarization of the cytoskeleton. Science 299:
1713–1716.
Iijima M, Huang YE, Devreotes P. (2002). Temporal and spatial
regulation of chemotaxis. Dev Cell 3: 469–478.
Ishidate T, Matsumine A, Toyoshima K, Akiyama T. (2000). The
APC-hDLG complex negatively regulates cell cycle progression
from the G0/G1 to S phase. Oncogene 19: 365–372.
Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S
et al. (2007). Chemotherapy-resistant human AML stem cells home
to and engraft within the bone-marrow endosteal region. Nat
Biotechnol 25: 1315–1321.
Januschke J, Gonzalez C. (2008). Drosophila asymmetric division,
polarity and cancer. Oncogene 27: 6994–7002.
Javier RT. (2008). Cell polarity proteins: common targets for
tumorigenic human viruses. Oncogene 27: 7031–7046.
Jones P, May G, Healy L, Brown J, Hoyne G, Delassus S et al. (1998).
Stromal expression of Jagged 1 promotes colony formation by fetal
hematopoietic progenitor cells. Blood 92: 1505–1511.
Kallay LM, McNickle A, Brennwald PJ, Hubbard AL, Braiterman
LT. (2006). Scribble associates with two polarity proteins, Lgl2 and
Vangl2, via distinct molecular domains. J Cell Biochem 99: 647–664.
Kamei Y, Kito K, Takeuchi T, Imai Y, Murase R, Ueda N et al.
(2007). Human scribble accumulates in colorectal neoplasia in
association with an altered distribution of beta-catenin. Hum Pathol
38: 1273–1281.
Kemphues KJ, Priess JR, Morton DG, Cheng NS. (1988). Identification of genes required for cytoplasmic localization in early C.
elegans embryos. Cell 52: 311–320.
Kiel MJ, Morrison SJ. (2008). Uncertainty in the niches that maintain
haematopoietic stem cells. Nat Rev Immunol 8: 290–301.
Klezovitch O, Fernandez TE, Tapscott SJ, Vasioukhin V. (2004). Loss
of cell polarity causes severe brain dysplasia in Lgl1 knockout mice.
Genes Dev 18: 559–571.
Knoblich JA. (2008). Mechanisms of asymmetric stem cell division.
Cell 132: 583–597.
Krummel MF, Macara I. (2006). Maintenance and modulation of T
cell polarity. Nat Immunol 7: 1143–1149.
Oncogene
Polarity and asymmetric cell division in leukemia
ED Hawkins and SM Russell
7016
Ladi E, Yin X, Chtanova T, Robey EA. (2006). Thymic microenvironments for T cell differentiation and selection. Nat Immunol 7:
338–343.
Langevin J, Le Borgne R, Rosenfeld F, Gho M, Schweisguth F,
Bellaiche Y. (2005). Lethal giant larvae controls the localization
of notch-signaling regulators numb, neuralized, and Sanpodo
in Drosophila sensory-organ precursor cells. Curr Biol 15:
955–962.
le Viseur C, Hotfilder M, Bomken S, Wilson K, Rottgers S, Schrauder
A et al. (2008). In childhood acute lymphoblastic leukemia, blasts at
different stages of immunophenotypic maturation have stem cell
properties. Cancer Cell 14: 47–58.
Lee CY, Andersen RO, Cabernard C, Manning L, Tran KD, Lanskey
MJ et al. (2006a). Drosophila Aurora-A kinase inhibits neuroblast
self-renewal by regulating aPKC/Numb cortical polarity and
spindle orientation. Genes Dev 20: 3464–3474.
Lee CY, Robinson KJ, Doe CQ. (2006b). Lgl, Pins and aPKC regulate
neuroblast self-renewal versus differentiation. Nature 439: 594–598.
Lee M, Vasioukhin V. (2008). Cell polarity and cancer-cell and
tissue polarity as a non-canonical tumor suppressor. J Cell Sci 121:
1141–1150.
Lee OK, Frese KK, James JS, Chadda D, Chen ZH, Javier RT et al.
(2003). Discs-Large and Strabismus are functionally linked to
plasma membrane formation. Nat Cell Biol 5: 987–993.
Li L, Neaves WB. (2006). Normal stem cells and cancer stem cells: the
niche matters. Cancer Res 66: 4553–4557.
Li Z, Hannigan M, Mo Z, Liu B, Lu W, Wu Y et al. (2003).
Directional sensing requires G beta gamma-mediated PAK1 and
PIX alpha-dependent activation of Cdc42. Cell 114: 215–227.
Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM et al.
(2004). Activation of the Wnt signaling pathway in chronic
lymphocytic leukemia. Proc Natl Acad Sci USA 101: 3118–3123.
Ludford-Menting MJ, Oliaro J, Sacirbegovic F, Cheah ET, Pedersen
N, Thomas SJ et al. (2005). A network of PDZ-containing proteins
regulates T cell polarity and morphology during migration and
immunological synapse formation. Immunity 22: 737–748.
Martin-Belmonte F, Gassama A, Datta A, Yu W, Rescher U, Gerke V
et al. (2007). PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42. Cell 128:
383–397.
Metcalf D, Wiadrowski M. (1966). Autoradiographic analysis of
lymphocyte proliferation in the thymus and in thymic lymphoma
tissue. Cancer Res 26: 483–491.
Mikesch JH, Steffen B, Berdel WE, Serve H, Muller-Tidow C. (2007).
The emerging role of Wnt signaling in the pathogenesis of acute
myeloid leukemia. Leukemia 21: 1638–1647.
Mizumoto K, Sawa H. (2007a). Cortical beta-catenin and APC
regulate asymmetric nuclear beta-catenin localization during asymmetric cell division in C. elegans. Dev Cell 12: 287–299.
Mizumoto K, Sawa H. (2007b). Two betas or not two betas: regulation
of asymmetric division by beta-catenin. Trends Cell Biol 17:
465–473.
Montcouquiol M, Rachel RA, Lanford PJ, Copeland NG, Jenkins
NA, Kelley MW. (2003). Identification of Vangl2 and Scrb1 as
planar polarity genes in mammals. Nature 423: 173–177.
Moreno-Bueno G, Portillo F, Cano A. (2008). Transcriptional
regulation of cell polarity in EMT and cancer. Oncogene 27:
6958–6969.
Morrison SJ, Kimble J. (2006). Asymmetric and symmetric stem-cell
divisions in development and cancer. Nature 441: 1068–1074.
Morrison SJ, Spradling AC. (2008). Stem cells and niches: mechanisms
that promote stem cell maintenance throughout life. Cell 132:
598–611.
Mortreux F, Gabet AS, Wattel E. (2003). Molecular and cellular
aspects of HTLV-1 associated leukemogenesis in vivo. Leukemia 17:
26–38.
Ngo NT, Lampert IA, Naresh KN. (2008). Bone marrow trephine
morphology and immunohistochemical findings in chronic myelomonocytic leukaemia. Br J Haematol 141: 771–781.
Nimer SD. (2008). Myelodysplastic syndromes. Blood 111: 4841–4851.
Oncogene
Nishio M, Watanabe K, Sasaki J, Taya C, Takasuga S, Iizuka R et al.
(2007). Control of cell polarity and motility by the PtdIns(3, 4, 5)P3
phosphatase SHIP1. Nat Cell Biol 9: 36–44.
Norberg B, Brandt L, Von Mecklenburg C, Rydgren L, Sternstam M.
(1977). Hand-mirror blast cells in acute leukemia. Lancet 1: 957.
Ohshiro T, Yagami T, Zhang C, Matsuzaki F. (2000). Role of cortical
tumour-suppressor proteins in asymmetric division of Drosophila
neuroblast. Nature 408: 593–596.
Okita K, Ichisaka T, Yamanaka S. (2007). Generation of germlinecompetent induced pluripotent stem cells. Nature 448: 313–317.
Oliaro J, Pasam A, Waterhouse NJ, Browne KA, Ludford-Menting
MJ, Trapani JA et al. (2006). Ligation of the cell surface receptor,
CD46, alters T cell polarity and response to antigen presentation.
Proc Natl Acad Sci USA 103: 18685–18690.
Orgogozo V, Schweisguth F, Bellaiche Y. (2002). Binary cell death
decision regulated by unequal partitioning of Numb at mitosis.
Development 129: 4677–4684.
Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M et al.
(2007). Mutational loss of PTEN induces resistance to NOTCH1
inhibition in T-cell leukemia. Nat Med 13: 1203–1210.
Peng CY, Manning L, Albertson R, Doe CQ. (2000). The tumoursuppressor genes lgl and dlg regulate basal protein targeting in
Drosophila neuroblasts. Nature 408: 596–600.
Petropoulos K, Arseni N, Schessl C, Stadler CR, Rawat VP,
Deshpande AJ et al. (2008). A novel role for Lef-1, a central
transcription mediator of Wnt signaling, in leukemogenesis. J Exp
Med 205: 515–522.
Rattis FM, Voermans C, Reya T. (2004). Wnt signaling in the stem cell
niche. Curr Opin Hematol 11: 88–94.
Real E, Faure S, Donnadieu E, Delon J. (2007). Cutting edge: atypical
PKCs regulate T lymphocyte polarity and scanning behavior.
J Immunol 179: 5649–5652.
Reya T, Morrison SJ, Clarke MF, Weissman IL. (2001). Stem cells,
cancer, and cancer stem cells. Nature 414: 105–111.
Roegiers F, Jan LY, Jan YN. (2005). Regulation of membrane
localization of Sanpodo by lethal giant larvae and neuralized in
asymmetrically dividing cells of Drosophila sensory organs. Mol Biol
Cell 16: 3480–3487.
Roman-Gomez J, Cordeu L, Agirre X, Jimenez-Velasco A, San JoseEneriz E, Garate L et al. (2007). Epigenetic regulation of Wnt-signaling
pathway in acute lymphoblastic leukemia. Blood 109: 3462–3469.
Rothenberg EV, Moore JE, Yui MA. (2008). Launching the T-celllineage developmental programme. Nat Rev Immunol 8: 9–21.
Round JL, Tomassian T, Zhang M, Patel V, Schoenberger SP, Miceli
MC. (2005). Dlgh1 coordinates actin polymerization, synaptic T cell
receptor and lipid raft aggregation, and effector function in T cells.
J Exp Med 201: 419–430.
Russell S. (2008). How polarity shapes the destiny of T cells. J Cell Sci
121: 131–136.
Sainte-Marie G, Leblond CP. (1965). Elaboration of a model for the
formation of lymphocytes in the thymic cortex of young adult rats.
Blood 26: 765–783.
Sanada K, Tsai LH. (2005). G protein betagamma subunits and AGS3
control spindle orientation and asymmetric cell fate of cerebral
cortical progenitors. Cell 122: 119–131.
Savona M, Talpaz M. (2008). Getting to the stem of chronic myeloid
leukaemia. Nat Rev Cancer 8: 341–350.
Schlessinger K, McManus EJ, Hall A. (2007). Cdc42 and noncanonical
Wnt signal transduction pathways cooperate to promote cell
polarity. J Cell Biol 178: 355–361.
Schumacher HR, Champion JE, Thomas WJ, Pitts LL, Stass SA.
(1979). Acute lymphoblastic leukemia—hand mirror variant. An
analysis of a large group of patients. Am J Hematol 7: 11–17.
Siegrist SE, Doe CQ. (2005). Microtubule-induced Pins/Galphai
cortical polarity in Drosophila neuroblasts. Cell 123: 1323–1335.
Sneddon JB, Werb Z. (2007). Location, location, location: the cancer
stem cell niche. Cell Stem Cell 1: 607–611.
Staal FJ, Luis TC, Tiemessen MM. (2008). WNT signalling in the
immune system: WNT is spreading its wings. Nat Rev Immunol 8:
581–593.
Polarity and asymmetric cell division in leukemia
ED Hawkins and SM Russell
7017
Steelman LS, Abrams SL, Whelan J, Bertrand FE, Ludwig DE,
Basecke J et al. (2008). Contributions of the Raf/MEK/ERK, PI3K/
PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Leukemia
22: 686–707.
Stephenson LM, Sammut B, Graham DB, Chan-Wang J, Brim KL,
Huett AS et al. (2007). DLGH1 is a negative regulator of
T-lymphocyte proliferation. Mol Cell Biol 27: 7574–7581.
Stinchcombe JC, Griffiths GM. (2007). Secretory mechanisms in cellmediated cytotoxicity. Annu Rev Cell Dev Biol 23: 495–517.
Takano H, Ema H, Sudo K, Nakauchi H. (2004). Asymmetric division
and lineage commitment at the level of hematopoietic stem cells:
inference from differentiation in daughter cell and granddaughter
cell pairs. J Exp Med 199: 295–302.
Tanegashima K, Zhao H, Dawid IB. (2008). WGEF activates Rho in
the Wnt-PCP pathway and controls convergent extension in
Xenopus gastrulation. EMBO J 27: 606–617.
Thiery JP, Sleeman JP. (2006). Complex networks orchestrate
epithelial–mesenchymal transitions. Nat Rev Mol Cell Biol 7:
131–142.
Thomas M, Narayan N, Pim D, Tomaic V, Massimi P, Nagasaka K
et al. (2008). Human papillomaviruses, cervical cancer and cell
polarity. Oncogene 27: 7018–7030.
Toyoshima F, Matsumura S, Morimoto H, Mitsushima M, Nishida E.
(2007). PtdIns(3, 4, 5)P3 regulates spindle orientation in adherent
cells. Dev Cell 13: 796–811.
Van Keymeulen A, Wong K, Knight ZA, Govaerts C, Hahn KM,
Shokat KM et al. (2006). To stabilize neutrophil polarity, PIP3 and
Cdc42 augment RhoA activity at the back as well as signals at the
front. J Cell Biol 174: 437–445.
Varnum-Finney B, Purton LE, Yu M, Brashem-Stein C, Flowers D,
Staats S et al. (1998). The Notch ligand, Jagged-1, influences the
development of primitive hematopoietic precursor cells. Blood 91:
4084–4091.
Verburgh E, Achten R, Maes B, Hagemeijer A, Boogaerts M, De
Wolf-Peeters C et al. (2003). Additional prognostic value of bone
marrow histology in patients subclassified according to the
International Prognostic Scoring System for myelodysplastic
syndromes. J Clin Oncol 21: 273–282.
von Stein W, Ramrath A, Grimm A, Muller-Borg M, Wodarz A.
(2005). Direct association of Bazooka/PAR-3 with the lipid
phosphatase PTEN reveals a link between the PAR/aPKC complex
and phosphoinositide signaling. Development 132: 1675–1686.
Wang F, Herzmark P, Weiner OD, Srinivasan S, Servant G, Bourne
HR. (2002). Lipid products of PI(3)Ks maintain persistent
cell polarity and directed motility in neutrophils. Nat Cell Biol 4:
513–518.
Wang SF, Aoki M, Nakashima Y, Shinozuka Y, Tanaka H, Taniwaki
M et al. (2008). Development of Notch-dependent T-cell leukemia
by deregulated Rap1 signaling. Blood 111: 2878–2886.
Weerkamp F, van Dongen JJ, Staal FJ. (2006). Notch and Wnt
signaling in T-lymphocyte development and acute lymphoblastic
leukemia. Leukemia 20: 1197–1205.
Weng AP, Ferrando AA, Lee W, Morris IV JP, Silverman LB,
Sanchez-Irizarry C et al. (2004). Activating mutations of NOTCH1
in human T cell acute lymphoblastic leukemia. Science 306:
269–271.
Wernig M, Meissner A, Foreman R, Brambrink T, Ku M,
Hochedlinger K et al. (2007). In vitro reprogramming of fibroblasts
into a pluripotent ES-cell-like state. Nature 448: 318–324.
Wikramanayake AH, Hong M, Lee PN, Pang K, Byrum CA, Bince
JM et al. (2003). An ancient role for nuclear beta-catenin in the
evolution of axial polarity and germ layer segregation. Nature 426:
446–450.
Wu H, Feng W, Chen J, Chan LN, Huang S, Zhang M. (2007a). PDZ
domains of Par-3 as potential phosphoinositide signaling integrators. Mol Cell 28: 886–898.
Wu M, Kwon HY, Rattis F, Blum J, Zhao C, Ashkenazi R et al.
(2007b). Imaging hematopoietic precursor division in real time. Cell
Stem Cell 1: 541–554.
Xavier R, Rabizadeh S, Ishiguro K, Andre N, Ortiz JB, Wachtel H
et al. (2004). Discs large (Dlg1) complexes in lymphocyte activation.
J Cell Biol 166: 173–178.
Xie T, Li L. (2007). Stem cells and their niche: an inseparable
relationship. Development 134: 2001–2006.
Xue L, Nolla H, Suzuki A, Mak TW, Winoto A. (2008). Normal
development is an integral part of tumorigenesis in T cell-specific
PTEN-deficient mice. Proc Natl Acad Sci USA 105: 2022–2027.
Yamashita YM, Jones DL, Fuller MT. (2003). Orientation of
asymmetric stem cell division by the APC tumor suppressor and
centrosome. Science 301: 1547–1550.
Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H
et al. (2006). Pten dependence distinguishes haematopoietic stem
cells from leukaemia-initiating cells. Nature 441: 475–482.
Yin X, Ladi E, Chan SW, Li O, Killeen N, Kappes DJ et al. (2007).
CCR7 expression in developing thymocytes is linked to the CD4
versus CD8 lineage decision. J Immunol 179: 7358–7364.
Yoshida S, Higuchi M, Shoji T, Yoshita M, Ishioka K, Takahashi M
et al. (2008). Knockdown of synapse-associated protein Dlg1
reduces syncytium formation induced by human T-cell leukemia
virus type 1. Virus Genes 37: 9–15.
Ysebaert L, Chicanne G, Demur C, De Toni F, Prade-Houdellier N,
Ruidavets JB et al. (2006). Expression of beta-catenin by acute
myeloid leukemia cells predicts enhanced clonogenic capacities and
poor prognosis. Leukemia 20: 1211–1216.
Zhang J, Grindley JC, Yin T, Jayasinghe S, He XC, Ross JT et al.
(2006). PTEN maintains haematopoietic stem cells and acts in
lineage choice and leukaemia prevention. Nature 441: 518–522.
Zhao C, Blum J, Chen A, Kwon HY, Jung SH, Cook JM et al. (2007).
Loss of beta-catenin impairs the renewal of normal and CML stem
cells in vivo. Cancer Cell 12: 528–541.
Zigmond SH, Levitsky HI, Kreel BJ. (1981). Cell polarity: an
examination of its behavioral expression and its consequences
for polymorphonuclear leukocyte chemotaxis. J Cell Biol 89:
585–592.
Oncogene