*Department of Pediatric
Cancer Institute and Harvard
Medical School, Boston,
Massachusetts 02115, USA.
‡Department of Cancer
Immunology and AIDS, Dana-
Farber Cancer Institute and
Harvard Medical School,
Correspondence to A.T.L.
13 April 2006
Notch 1 activation in the molecular
pathogenesis of T-cell acute
Clemens Grabher*, Harald von Boehmer‡ and A. Thomas Look*
Abstract | The chromosomal translocation t(7;9) in human T-cell acute lymphoblastic
leukaemia (T-ALL) results in deregulated expression of a truncated, activated form of Notch 1
(TAN1) under the control of the T-cell receptor-β (TCRB) locus. Although TAN1 efficiently
induces T-ALL in mouse models, t(7;9) is present in less than 1% of human T-ALL cases. The
recent discovery of novel activating mutations in NOTCH1 in more than 50% of human T-ALL
samples has made it clear that Notch 1 is far more important in human T-ALL pathogenesis
than previously suspected.
T-cell acute lymphoblastic leukaemia (T-ALL) is a
malignancy of thymocytes that develops mainly in
children and adolescents but also arises in adults, and
affects about 1,500 people per year in the United
States. This aggressive tumour is characterized by high
peripheral-blood-cell counts, increased numbers of blast
cells, CNS dissemination and, more often than not, large
mediastinal masses that cause tracheal compression and
respiratory distress at diagnosis. Although T-ALL often
arises in the thymus, it spreads throughout the body
and, without therapy, is rapidly fatal. Current treatment
for T-ALL consists mainly of multi-agent combination
chemotherapy. Over the past 50 years, treatment success
rates for paediatric ALL have markedly improved, from
a median survival of 2 months from diagnosis to overall
survival rates of nearly 80% (REF. 1). However, less success
has been achieved in the treatment of adults with T-ALL,
with long-term survival rates of only 30% to 40% among
patients under 60 years of age, and decreasing to about
10% in patients over 60 years of age2–5.
Leukaemic transformation of developing thymocytes
is caused by multistep mutagenesis involving various
genetic alterations that shift normal cells into uncon-
trolled growth and clonal expansion. These changes can
affect cell-cycle control, stem-cell maintenance and cell
proliferation, differentiation or survival. Cytogenetic
analyses and the molecular cloning of chromosomal
translocation breakpoints led to the discovery of
transcriptional regulatory proteins that are aberrantly
expressed in T-ALL owing to the juxtapositioning of
their respective genes next to strong T-cell receptor
(TCR) gene enhancers and promoters, without any obvi-
ous alterations in protein structure (with the exception of
TAN1, or truncated activated Notch 1). In general, these
translocated proteins have important functions during
normal embryogenesis, although many are not essential
for the development of normal thymocytes6 (TABLE 1). So,
many cases of T-ALL seem to result from the thymocyte-
specific aberrant expression of proteins that normally
function primarily in non-lymphoid tissues.
Aberrant protein expression in T-ALL
The initial identification of genomic abnormalities in
T-ALL cases demonstrated that most, although not
all, involved promoter and enhancer elements of TCR
genes and a relatively small number of developmen-
tally important transcription-factor genes, including
MYC, the entire HOXA cluster, HOX11 (also known as
T-cell-leukaemia homeobox 1 (TLX1)), HOX11L2 (also
known as TLX3), TAL1 (T-cell acute lymphocytic leu-
kaemia 1), TAL2, LYL1 (leukaemia, lymphoid 1), LMO1
(LIM-domain only) and LMO2 (TABLE 1; FIG. 1).
The proto-oncogene MYC is juxtaposed adjacent
to the TCRA gene in about 2% of T-ALL cases, result-
ing in overexpression of MYC. Disease progression in
these cases is rapid, and the response to conventional
therapy is poor7. TAL1 is an essential factor for the
development of haematopoietic lineages. Similarly,
recent data indicates that LYL1 might also function in
haematopoiesis8. Rearrangements of the genes encod-
ing these proteins to the TCRB or TCRA/D locus
result in deregulated protein expression. Alterations
of the TAL1 locus are found in up to 25% of all T-ALL
cases, but only about 3% involve TCR loci, whereas
the remainder have a deletion that places TAL1 under
the control of the SIL gene promoter9. The oncogenic
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Immature thymocytes that do
not express CD4 or CD8 cell-
surface markers and have not
yet undergone gene
rearrangement to produce a
functional TCR. Double
negative thymocytes can be
divided up into 4 subsets
(DN1–DN4) that reflect their
Extra-chromosomal DNA (such
as a plasmid). Amplification of
a DNA segment followed by
circularization can result in the
generation of episomal DNA
(for example the NUP214–
ABL1 gene fusion).
potential of TAL1 is probably due to its inhibitory
interaction with the E2A transcription factor10–13.
Subtypes of T-ALL that are defined by TAL1 or LYL1
expression are associated with a poor prognosis, which
might be explained by the concomitant upregula-
tion of anti-apoptotic genes that confer resistance to
chemotherapy14,15. The LMO1 and LMO2 genes, which
are normally expressed only in early double-negative
T-cells (LMO2) or not at all (LMO1), are frequently
translocated adjacent to the TCRA/D locus16. Ectopic
overexpression of these LIM-domain-only proteins is
often found in cases of T-ALL that also show deregu-
lated expression of TAL1 or LYL1. In fact, LMO2 forms
a heteromeric DNA-binding complex with TAL1 and
other proteins, and these two proteins have been
shown to cooperate in leukaemogenesis17,18.
The class I Hox genes, which are organized as four
distinct clusters, are essential for anterior–posterior
patterning and differentiation during embryogenesis,
and they also regulate haematopoiesis19. So far, only
the HOXA cluster has been associated with T-ALL20,21.
A chromosomal inversion juxtaposes the TCRB locus
next to the HOXA cluster, resulting in deregulated
expression of the entire cluster and the genes HOXA10
and HOXA11 in particular. Both of these genes are
expressed in developing thymocytes, indicating a func-
tion in normal T-cell development22,23. The class II
orphan Hox genes are dispersed throughout the entire
genome. HOX11 and HOX11L2, which are members
of the class II group of Hox genes, are frequent targets
of genomic alterations in T-ALL. Hox11 is required
for spleen development in mice but is normally not
expressed in T-cells24,25. Activation of HOX11 in T-cells,
by chromosomal translocation to the TCRA or TCRB
locus, probably promotes transformation by interfering
with normal T-cell-specific regulatory cascades. HOX11
expression is associated with a favourable prognosis,
possibly owing to concomitant downregulation of anti-
apoptotic genes14. In almost 20% of childhood T-ALL
cases, HOX11L2 is activated by a translocation near the
BCL11B locus, a gene that is highly expressed during
T-cell differentiation26. The HOX11- and HOX11L2-
expression profiles of T-ALL samples are very similar,
indicating that similar leukaemogenic mechanisms
might underlie these cases. Although some studies indi-
cate a poor prognosis for patients with T-ALL whose
tumour cells overexpress HOX11L2, more intensive
therapy seems to improve the therapeutic response
Some chromosomal translocations that have been
identified in T-ALL result in fusion proteins. MLL
(mixed-lineage leukaemia)–ENL fusions in T-cell
leukaemia are associated with an early thymocyte-
differentiation arrest and lead to increased expression
of important Hox genes, such as HOXA9, HOXA10
and HOXC6, as well as the Hox-gene regulator MEIS1
(myeloid ectopic integration site 1) (REF. 16). CALM
(clathrin-assembly protein)–AF10 fusions were iden-
tified in approximately 10% of T-ALL patients with
immature T-cell lymphoblasts29,30. Little is known
about the function of this fusion protein, although both
CALM and AF10 have been identified as fusion partners
of MLL31,32. Three ABL1 fusions have been reported in
T-ALL: ETV6–ABL1, EML1 (echinoderm-microtubule-
associated-protein-like 1)–ABL1 and NUP214–ABL1
(REFS 33–35). NUP214–ABL1 is found on episomal
elements in about 6% of T-ALL patients and is asso-
ciated with increased expression of HOX11 and
HOX11L2 (REF. 33). Interestingly, BCR–ABL fusions
are rare in human T-ALL despite their prominent
roles in chronic myeloid leukaemia (CML) and
early B-lineage ALL33 . However, many murine
At a glance
• T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive blood cancer that affects about 1,500 people per year in
the United States. Significant advances have been made in the development of effective therapies for this otherwise
rapidly fatal disease, which is most common in children and adolescents.
• T-ALL can be classified into at least five different subtypes based on the activation of specific T-ALL oncogenes and
associated gene-expression profiles that correlate with the stage of arrest in T-cell development.
• The NOTCH1 gene is expressed in haematopoietic stem cells (HSCs) and controls several steps in thymocyte
specification and differentiation. Chromosomal alterations that juxtapose a truncated, activated form of NOTCH 1
(TAN1) with the T-cell receptor-β (TCRB) locus occur in less than 1% of all T-ALL cases.
• Somatic activating mutations of NOTCH1 have been identified in more than 50% of all T-ALL cases and are found in all
previously defined T-ALL subtypes. One set of mutations destabilizes the Notch heterodimerization domain, probably
facilitating ligand-independent pathway activation, whereas mutations that disrupt the intracellular PEST (polypeptide
enriched in proline, glutamate, serine and threonine) domain might function by increasing the half-life of
transcriptionally active intracellular Notch 1 (ICN1).
• The high prevalence of NOTCH1 mutations in T-ALL, and the dependence of T-ALL cases on Notch-1-pathway activation
for unrestricted proliferation render this protein an excellent candidate for pharmacological intervention with
• Studies of Notch 1 in the induction of T-ALL, using murine and zebrafish T-ALL models, might lead to the discovery of
pharmacological inhibitors that specifically target other components in the Notch 1 pathway.
• Emerging knowledge of the specific gene-expression profiles associated with T-ALL subtypes, the important function of
Notch 1 in T-cell leukaemogenesis, and the development of novel, specific inhibitors should stimulate the development
of disease-specific treatments that increase survival rates and improve the quality of life of patients with T-ALL.
348 | MAY 2006 | VOLUME 6
© 2006 Nature Publishing Group
Bcr–Abl models develop T-cell neoplasms36. The rare
ETV6–JAK2 fusion provides a link between T-ALL
and the JAK tyrosine-kinase family that is important
for development37. Originally identified in a paedi-
atric T-ALL sample, ETV6–JAK2 has been shown
to induce leukaemia in a transgenic mouse model38.
Finally, different components of the TCR-signalling
pathway — such as the SRC-family tyrosine kinase
LCK (lymphocyte-specific protein tyrosine kinase),
and NRAS — have been identified as targets of acti-
vating mutations or translocations that result in their
overexpression, which confers a proliferative and
survival advantage on thymocytes that can lead to
Table 1 | Genomic alterations in T-cell acute leukaemia
Type of proteinT-ALL
Genes affected Normal developmental
Homeodomain Inversion to TCRB
to TCRB locus;
Homeodomain HOX11L2 t(5;14)(q35;q32);
CNS development 26,158
bHLHBHLHB1t(14;21)(q11;q22) CNS development159
bHLH LYL1t(7;19)(q35;p13) Haematopoiesis 160
bHLH TAL1 t(1;14)(p32;q11) Embryonic HSC
bHLH TAL2 t(7;9)(q35;q34)163
bHLH/Lzip MYCt(8;14)(q24;q11)Cell growth and apoptosis164–166
LIM domainLMO1t(11;14)(p15;q11) Unknown167,168
LIM domain LMO2t(11;14)(p13;q11);
EML1–ABL1 t(9;14)(q34;q32)Cytoskeleton (EML1)–nuclear
immune response (JAK2)
nuclear signalling (ABL1)
ETV6–JAK2t(9;12)(p24;p13) Gene fusion 37
ETV6–ABL1 t(9;12)(q34;p13)Gene fusion 35
LCKt(1;7)(p34;q34) Translocation to
to TCRB locus;
Notch receptorNOTCH1 * t(7;9)(q34;q34.3)
T-cell fate 44
t(4;11)(q21;p15) Nuclear transport (NUP98)–
Ras activation (RAP1GDS1)
Nuclear transport (NUP214)–
nuclear signalling (ABL1)
Clathrin assembly (CALM)–
episomal Gene fusion 33
t(10;11)(p13;q21)Gene fusion 30,172
*This can also include the truncated, activated form of Notch 1. bHLH, basic helix-loop-helix; CALM, clathrin-assembly protein;
CC, coiled-coil; ENTH, epsin N-terminal homologous; ETS, erythroblast-transformation-specific domain; GEF, guanine-nucleotide-
exchange factor; HSC, haematopoietic stem cell; LIM, zinc-binding domain that is present in LIN11, ISL1 and MEC3; LMO, LIM-
domain only; LYL, leukaemia, lymphoid 1; Lzip, leucine zipper; RAP1GDS1, RAP1, GTP–GDP dissociation stimulator 1; T-ALL, T-cell
acute lymphoblastic leukaemia; TAL1, T-cell acute lymphocytic leukaemia 1; TCR, T-cell receptor.
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t(11;14), t(7;11) 7%
t(7;10), t(10;14) 7%
Other 7(q35) or
14(q11) abnormalities 3%
No TCR translocations 80%
HD + PEST 16%
NOTCH1 encodes a regulatory transmembrane recep-
tor. To date, it is the only example of a gene that is crucial
in the control of normal T-cell fate that is truncated by
an exceedingly rare translocation. This translocation
juxtaposes the C terminus of NOTCH1 adjacent to the
TCRB locus, leading to overexpression of truncated
NOTCH1 transcripts44 that are potent inducers of T-ALL
in murine models. Two important questions are raised by
the cytogenetic and molecular-genetic findings discussed
above and listed in TABLE 1. First, is there a wider role
for NOTCH1 in T-ALL pathogenesis beyond that pre-
dicted by its rare translocation to the TCRB locus? And
second, how are NOTCH1 and other genes integrated into
multistep pathways leading to T-ALL? Recent research
that addresses these questions in significant ways will be
the subject of the following sections. We will also discuss
the clinical impact of recent results as well as strategies that
could be used to identify oncogenic partners of Notch 1
and suppressors of Notch-1-induced T-ALL.
The Notch pathway
T. H. Morgan first described a Drosophila melanogaster
mutant strain with ‘notched’ wings in 1917 (REF. 45). The
gene that is responsible for this phenotype was identified
almost 70 years later as Drosophila Notch (dNotch)46. The
Notch signalling pathway is one of the key pathways in
the development of multicellular organisms, as it con-
trols cell fate by regulating cell proliferation, survival,
positioning in the organism, and differentiation47. Notch
signalling is also important in adults, in which it regu-
lates stem-cell maintenance, binary cell-fate decisions,
such as the T- or B-lymphocyte lineage decision, and
differentiation in self-renewing organs48.
The first human orthologue of dNotch, NOTCH1,
was identified in T-ALL patients with the chromosomal
translocation t(7;9)(q34;q34.3)44, and the full-length
gene was subsequently shown to be indispensable for
normal T-lymphopoiesis49–54. Aberrant Notch signalling
interferes with embryonic development and has been
detected in various human diseases, including several
types of cancer44,55–63. Given the correlation of Notch sig-
nalling with a plethora of different events during embryo-
genesis in multicellular organisms, it is not surprising
that the outcome of Notch activation crucially depends
on cellular context, timing and gene dose. Accordingly,
Notch might function as an oncogene in some tissues
and as a tumour suppressor in others44,55.
Notch 1 signalling in thymocyte development
The Notch signalling pathway is complex and involves
the coordinated activities of many different molecules.
A detailed description of the Notch signalling pathway
is shown in FIG. 2. In brief, Notch is synthesized in the
endoplasmic reticulum (ER) as a single protein (pre-
Notch), which is transported to the Golgi network,
where several post-translational modifications occur.
Among them is the first of three proteolytic cleavages
(S1), which separates the extracellular from the intra-
cellular portion of the receptor. Following S1 cleavage,
the Notch receptor heterodimer is transported to the
membrane. Following ligand interaction, the intracel-
lular domain (ICN) translocates to the nucleus and
activates the transcription of target genes (FIG. 2).
Notch 1 signalling is crucial for T-cell fate speci-
fication, namely the T- versus B-cell lineage choice
in early haematopoietic progenitors. Notch 1 signal-
ling is required for commitment of the earliest T-cell
progenitors in the thymus and promotes their prolif-
eration, differentiation and survival64–67. Inactivation
of Notch 1 signalling in bone-marrow precursors or
early lymphoid progenitors results in the generation of
B cells and prevents the development of T cells54,68–71.
Conversely, constitutive activation of Notch 1 inhibits
B-cell development and results in extrathymic T-cell
development72–74. T cells undergo a further commitment
when they rearrange their TCR genes into the αβ- or
γδ-lineage. Notch 1 might have a dual function in this
lineage commitment, in which the γδ-lineage could be
favoured by activated Notch 1 signalling within a small
developmental window in early thymocyte populations,
whereas inhibition of Notch 1 signalling in slightly
Figure 1 | Distribution of genomic aberrations and
NOTCH1 mutations in paediatric T-ALL. a | Distribution
of the most common translocations involving the T-cell
receptor (TCR) loci among 201 cases of paediatric T-cell
acute lymphoblastic leukaemia (T-ALL). These
abnormalities reflect the presence of specific oncogenes
— such as LMO1 (LIM-domain only) and LMO2, HOX11,
TAL1 (T-cell acute lymphocytic leukaemia 1) and MYC —
that are leukaemogenic when misexpressed in T-cell
precursors. Other 7q35 or 14q11 abnormalities include
translocations of HOX11L2, BHLHB1, LYL1 (leukaemia,
lymphoid 1), TAL2, LCK (lymphocyte-specific protein
tyrosine kinase) and NOTCH1. The inv(7)(p15;q34)
inversion, which juxtaposes parts of the TCRB locus next to
the HOXA cluster is not included in the figure, but recent
data indicate that it occurs in ~5% of all T-ALL cases20,21.
b | Distribution of NOTCH1 mutations in 187 cases of
childhood T-ALL. Note that only 42% of cases do not show
these mutations. All of the most common T-ALL subtypes
contain NOTCH1 mutations (FIG. 5). The
heterodimerization domain (HD) and the PEST
(polypeptide enriched in proline, glutamate, serine and
threonine) destruction box in Notch 1 are affected by
mutations. WT, wild type. Part a is modified, with
permission, from REF. 173 © (2000) Elsevier Science.
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Glycosylation S1 cleavage
+ ER exit
Figure 2 | The Notch signalling pathway. a | The intracellular and extracellular domains of the Notch receptor
are synthesized as a single protein (pre-Notch). O-fucosyltransferase1 (OFUT1) functions as a chaperone and is
required for the transport of pre-Notch from the endoplasmic reticulum (ER) to the Golgi apparatus and for
fucosylation of glycosylated serine and threonine residues of the extracellular domain within the Golgi141.
b | Glycosylation of these residues is carried out by members of the Fringe family (radical, manic and lunatic).
A Furin-like convertase cleaves pre-Notch into the extracellular and intracellular domain (S1 cleavage). This
results in a heterodimeric receptor with non-covalently associated domains that is transported to the plasma
membrane. c | The readout of receptor–ligand interaction is determined by the specific Fringe modifications that
were introduced earlier in the Golgi, which affect sensitivity to the DSL (Delta (DLL)–Serrate–Lag2) ligands.
Additionally, the E3 ubiquitin ligases, Mindbomb (MIB) and Neuralized-like (NEURL) promote the turnover of the
ligand and therefore contribute to productive ligand–receptor interactions. d | Ligand binding initiates two
successive proteolytic cleavages (S2 and S3). The first, mediated by an ADAM (a disintegrin and metalloproteinase
domain) proteinase, occurs in the extracellular domain. S2 cleavage allows access of the γ-secretase complex,
which is responsible for the second proteolytic cleavage (S3), which occurs within the transmembrane domain
and liberates the intracellular domain (ICN)131,142,143. e | The ICN translocates to the nucleus, where it interacts with
the IPT (immunoglobulin-like fold, plexins and transcription factors)-domain-containing CSL transcription factor.
Docking of the ankyrin-repeat domain of Notch to the Rel-homology region of the CSL protein generates a
composite binding surface for the recruitment of Mastermind-like proteins (MAML)144,145 (S. Blacklow, personal
communication). f | These interactions convert CSL from a transcriptional repressor to an activator by displacing
co-repressors (CoR) and histone deacetylases and recruiting histone acetyltransferases. MAML in turn recruits
additional co-activators (CoA), such as p300 (REFS 70,103,146–148). A few transcriptional targets of Notch have
been identified and include Hes1 (Hairy/enahncer of split), pre-T-cell-receptor-α (Ptrca), Deltex (DTX1), Nrarp
(Notch-regulated ankyrin-repeat protein), Cdkn1a and Cd25. Known regulators of Notch signalling include Numb,
NRARP, MINT (MSX2-interacting nuclear target) and Deltex. Numb suppresses Notch signalling, possibly by
preventing nuclear localization and targeting the ICN for degradation through the E3 ligase Itch149,150. Deltex is a
positive regulator of Notch in Drosophila 151 but can inhibit Notch signalling in mammals69. An alternative CSL-
independent pathway has been described in which Notch signalling is mediated through Deltex118. g | The
stability of nuclear ICN is regulated through its PEST (polypeptide enriched in proline, glutamate, serine and
threonine) domain. Binding of MAML to p300 and cyclin-dependent kinase 8 (CDK8) promotes hyperphosphoryla-
tion of the ICN PEST domain to facilitate ubiquitylation, probably by members of the SEL1 (also known as FBW7)
family of E3 ligases and the Itch E3 ligase, which target the ICN to the proteosome152,153. dnMAML, dominant-
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Bone marrow Thymic immigrantThymic T-cell precursorsLineages
HSC(s)? DN1(ETP) DN2-DN3
Notch 1 Notch 1
Thymocytes expressing both
the CD4 and CD8 cell-surface
markers after successful
rearrangement of a functional
later stages (DN3; FIG. 3) clearly blocks αβ-develop-
ment50–52,67,75,76. Most data that support a role for Notch
in T-cell lineage decisions are derived from knockout
or in vitro studies in the absence or presence of specific
Notch ligands. The exact role of Notch-receptor signal-
ling in αβ- versus γδ-lineage commitment is still under
debate and might be strictly regulated according to the
type of ligand and the exact stage of T-cell maturation.
Malignant thymocytes in Notch-1-associated leukaemia
are arrested at the double-positive stage of development or
earlier, indicating that this is the crucial phase in which
aberrant Notch signalling might contribute to cell trans-
formation (FIG. 3). Also, malignant thymocytes in most of
the identified T-ALL subtypes are committed to the αβ
lineage. Other Notch-regulated activities within mature,
circulating T cells will not be discussed in this Review,
but are discussed elsewhere77–81.
Although expression of Notch 2 is more pronounced
in haematopoietic stem cells (HSCs), Notch 1 activity
might also be required, in a cell-autonomous manner,
for the generation of HSCs from endothelial cells in
early embryonic haematopoiesis — however, Notch 1
activity seems to be dispensable during the later stages
of development82,83. Gain-of-function studies also indi-
cate a role for Notch 1 in promoting adult HSC main-
tenance, whereas studies that are based on complete
loss-of-function of Notch 1 or the CSL transcription
factor (also known as RBPSUH in mammals) show
no such evidence53,68,84–86. Interestingly, the results
of experiments in which components of the Notch
pathway were ‘knocked down’ by dominant-negative
forms of Mastermind-like (MAML) and CSL proteins
might argue for a self-renewal-promoting function of
Notch in concert with Wnt signalling87. One explana-
tion for these disparate observations might be found
in the inherently different experimental approaches
used by the investigators. However, effects of a domi-
nant-negative MAML have not been described in the
latter study in vivo. Moreover, the dominant-negative
CSL protein affects transcriptional activation as it
lacks DNA-binding activity, but it retains the ability
to bind to ICN. However, it is unclear whether DNA
binding is inherently required for CSL to function as
a transcriptional repressor in this context88,89. As the
repressor function of the CSL protein is not known
to require Notch, additional studies based on reduced
levels of Notch signalling are needed to clarify the role
of Notch in regulating the self-renewal potential of adult
HSCs and possibly leukaemic stem cells.
Aberrant activation of Notch 1 in T-ALL
The molecular breakpoints in the t(7;9)-associated
tumours all cluster within 100 base pairs of intron 24
of NOTCH1. So, most of the extracellular domain is
deleted, which results in a series of Notch 1 peptides of
different size, all of which are devoid of EGF repeats and
Notch/LIN12 repeats90 (FIG. 4). These truncated Notch 1
isoforms (for example, TAN1) are temporally and spa-
tially expressed in the manner of the TCRB locus and
most of them possess constitutive, ligand-independent
activity. Constitutive activation of Notch 1 signal-
ling in murine models provided direct evidence for
the transforming potential of this protein, when mice
transplanted with TAN1-expressing haematopoietic
progenitor cells developed T-cell leukaemia91–93. The
lymphoblasts in these induced T-ALLs were pheno-
typically similar to the double-positive lymphoblasts in
human t(7;9)-positive leukaemia. This demonstration
was followed by studies with transgenic mice expressing
dominant-active forms of Notch 1, by the identifica-
tion of additional Notch1 rearrangements in mice with
radiation-induced thymomas, and Notch1 mutations
Figure 3 | Notch 1 receptors in T-cell development. Notch 1 signalling might be involved in self-renewal of
haematopoietic stem cells (HSCs) and is essential for commitment to the T-lymphoid lineage. Jagged-1–Notch-1
interactions between stromal cells and HSCs in stem-cell niches might influence stem-cell self-renewal.
Subsequently, Notch 1 signalling is required for commitment of a subset of double-negative 1 (DN1) cells to early
thymocyte progenitors (ETPs) and for T-cell maturation up to the double-positive (DP) stage; the CD4 versus CD8
lineage commitment seems largely unaffected by Notch 1. T-cell precursors form in the bone marrow and migrate to
the thymus to become double-negative (DN) thymocytes. The identity of the so-called thymic immigrant is unknown.
Proliferation and differentiation of DN thymocytes occurs in the thymus. Rearrangement of T-cell receptor-β (TCRB)
genes (usually together with TCRG and TCRD genes) in such thymocytes is one of the first significant steps in
differentiation. If γδ rearrangement succeeds first, the cell is identified as a γδ T-cell. If the TCRB gene is rearranged
first, the cell becomes an αβ T-cell. β- and α-chain surrogates are then expressed on the cell surface together with
CD4 and CD8, making the cell a double-positive thymocyte. In addition to the Delta-like 1 (DLL1) or DLL4–Notch-1
interactions (D1) that are required for T-cell development, the differentiation of late DN T-cell precursors to DP T-cell
precursors also requires (pre-) TCR signalling.
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Ligand binding to Notch 1
initiates two successive
proteolytic cleavages (S2 and
S3). The S2 cleavage allows
access of the γ-secretase
complex, which is responsible
for the second proteolytic
cleavage (S3). This cleavage
liberates the intracellular
domain of Notch 1 (ICN1),
which translocates the nucleus
to activate gene transcription.
So, inhibition of the γ-secretase
complex prevents the
activation of Notch signalling
A motif that contains the
amino-acids proline (P),
glutamic acid (E), serine (S) and
threonine (T) that is involved in
targeting proteins for
degradation through the
in murine transgenic models of T-ALL94–98. All of these
animals rapidly developed highly aggressive immature
T-cell malignancies, reinforcing a causative role of
Notch 1 in human T-cell transformation.
Despite the efficiency of Notch 1 in inducing T-ALL
in murine models, it became clear that the rare t(7;9)
translocation could not, by itself, account for more than
a minor fraction of T-ALL cases99. Importantly, aber-
rant Notch signalling was subsequently found in several
human leukaemias and lymphomas that lacked genomic
rearrangements100–102, indicating that upregulated Notch
signalling might have a common role in human leu-
kaemogenesis. Moreover, the growth and survival of cell
lines established from Notch-1-induced murine T-ALLs
and from cases with the human t(7;9) translocation were
dependent on sustained Notch activity103. Definitive
evidence for a central role of Notch 1 in human T-ALL
came from a recent study in which somatic activating
mutations in NOTCH1 were found in more than 50%
of human T-ALL samples104. Moreover, when 30 human
T-ALL cell lines were screened for Notch 1 dependency
using a γ-secretase inhibitor, 5 showed a G0/G1 cell-cycle
arrest that could be rescued by viral expression of the
intracellular domain of Notch 1 (ICN1). Sequencing of
NOTCH1 alleles in these cell lines identified missense
mutations at conserved amino-acid positions in the
N- and C-terminal heterodimerization domains and
short insertions or deletions in the polypeptide enriched
in proline, glutamate, serine and threonine (PEST) domain,
resulting in partial or complete deletion of this domain,
in cis in the same NOTCH1 allele. In a study of primary
paediatric T-ALL, 54 of 96 clinical samples (56%) con-
tained at least one mutation in the heterodimerization
or PEST domains, and almost 16% had mutations in
both domains104. Reporter-gene assays indicated that
these mutations activate Notch 1 signalling and showed
a synergistic increase in transcriptional activity.
Although heterodimerization-domain mutations
caused a maximal 9-fold increase in luciferase activity,
and PEST domain truncations only a 2-fold increase,
the combination of both mutations in cis resulted in
an almost 40-fold increase in luciferase activity104.
These findings might explain the puzzling discrepancy
between the high efficacy of Notch 1 in inducing T-cell
leukaemia in mice and the rare occurrence of the t(7;9)
translocation. That is, the translocation can only occur
in a relatively small subset of T-cells that are undergo-
ing V-D-J recombination at the TCRB locus, whereas the
point mutations and frame shifts in the heterodimeri-
zation and PEST domains can occur at various stages
of haematopoietic development. NOTCH1 is expressed
in both HSCs and T-cell precursors, and therefore
might simultaneously induce T-cell differentiation
and increase the self-renewal capacity of early haema-
topoietic progenitors, resulting in T-ALL. Despite high
levels of expression of NOTCH2 in HSCs and the fact
that overexpression of the intracellular domains of
NOTCH1, NOTCH2 and NOTCH3 all cause T-ALL in
murine models, only NOTCH1 mutations have been
identified in all known molecular subtypes of T-ALL
so far83,175, rendering this gene a unifying target of
transforming activities in human T-ALL (FIGS 1, 5).
How do heterodimerization and PEST domain
mutations activate Notch 1? The heterodimeriza-
tion domain is required for stable association of the
extracellular and intracellular portions of the Notch 1
receptor and prevents ligand-independent signal-
ling105. In C. elegans, mutations in the heterodimeriza-
tion domains of the NOTCH1 orthologues Glp1 and
Lin12 also result in gain-of-function alleles106,107. It is
therefore likely that these mutations change the con-
formation of the heterodimerization domain and facili-
tate S3 cleavage, resulting in increased ICN1 liberation
and translocation to the nucleus in a ligand-independent
manner. Alternatively, some of the mutations that are
found in NOTCH1 might convey ligand-hypersen-
sitivity and increase S3 cleavage in the absence of
any destabilization or conformational change of het-
erodimerization (J. Aster, personal communication).
The PEST domain has been linked to the half-life of
ICN1 by virtue of its ability to control its turnover108.
Furthermore, C-terminal truncations of ICN1 accel-
erated the onset of tumorigenesis in transgenic mouse
models109,110. So, deletions of the PEST domain might
accentuate Notch 1 activity by increasing the half-life
of ICN1 in the nucleus.
The precise mechanisms by which Notch 1 causes
T-ALL are not yet fully elucidated. For example, no
Figure 4 | Notch 1 receptor mutations in human T-cell acute lymphoblastic
leukaemia. The human NOTCH1 gene consists of 34 exons (vertical bars) and spans
~50 kb. The transcriptional start site in exon 1 is denoted by an arrow. The t(7;9)
translocation, mapped in 3 patients to intron 24, truncates most of the extracellular part
of the protein, and results in an activated, GSI (γ-secretase inhibitor)-resistant form of the
intracellular domain of Notch 1 (ICN1). Heterodimerization domain (HD) mutations,
found in exons 26 and 27, affect the N- and C-terminal portions of the transmembrane
domain and are thought to facilitate S3 cleavage (by the γ-secretase complex) and the
release of the ICN1. PEST (polypeptide enriched in proline, glutamate, serine and
threonine) domain mutations are found in exon 34 and affect the half-life of ICN1. Many
human T-cell acute lymphoblastic leukaemia samples show highly leukaemogenic
mutations in both the heterodimerization and PEST domains. ANK, ankyrin repeats; EGF,
EGF-like repeats; LIN, LIN12 repeats; P, PEST domain; R, RAM domain; T, transmembrane
domain; TAD, transactivation domain; WT, wild-type. Figure modified, with permission,
from REF. 174 © (2004) Elsevier Science.
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© 2006 Nature Publishing Group
↑ Notch 1
↑ Notch 1
↑ Notch 1
↑ Notch 1
↑ Cyclin D3
↑ Notch 1
The TCRB locus contains V, D
and J segments, similar to
the immunoglobulin heavy-
chain locus, that are
rearranged into diverse
combinations that increase
the repertoire of antigens
recognized by the T-cell
Notch-1-induced B-cell malignancies have been
described so far, and NOTCH1 mutations in myeloid
leukaemias are very rare (T. Palomero, A. Ferrando
and A.T.L., unpublished observation), indicating that
ICN1 needs T-cell-specific cooperative signals to
induce transformation. This hypothesis is supported
by the failure of ICN1 overexpression to induce leu-
kaemia in cells that lack pre-TCR signalling, whereas
reconstitution of this signalling pathway restored the
oncogenic function of activated Notch 1 (REF. 93).
Notch 1 is directly involved in upregulation of the
pre-TCRα gene (Ptcra), but might not be absolutely
required to maintain its expression because Ptcra is
still expressed in T-cells with conditional deletions of
Notch1 or Rbpsuh .
Other factors such as Ikaros might also be sufficient
for Ptcra induction in the absence of CSL49,50,111. However,
two components of TCR signalling, Ras and LCK, have
been associated with leukaemogenesis. Ras can induce
Notch1, Dll1 (Delta1) and Psen1 (Presenilin1) transcrip-
tion, resulting in Notch-pathway activation, and Notch
activity is required for maintenance of the malignant
properties of Ras-transformed cells57. Interaction of the
Notch and LCK signalling pathways induces several
anti-apoptotic genes, which promote cell survival and
might increase the risk of acquiring additional onco-
genic mutations within the malignant clone112. Another
effector of pre-TCR signalling, the cell-cycle regulator
cyclin D3, is crucial for the proliferative burst of double-
negative thymocytes. Besides its role in normal T-cell
development, cyclin D3 also cooperates with Notch 1 in
As discussed above, inhibition of the transcription
factor E2A is important for the oncogenic activity of
TAL1 and LMO2. The E2A gene produces two helix-
loop-helix transcription factors, E12 and E47, that are
crucial for normal B- and T-cell lymphopoiesis, and
E2A-deficient mice develop T-cell lymphomas10. High
levels of E2A impose a developmental and proliferative
block in thymocytes at the pre-TCR checkpoint, and
downregulation of E2A activity by signalling through
the pre-TCR pathway releases this block114. Notch 1
can regulate E2A in a CSL-dependent manner through
pre-TCR-signalling that involves, at least in part, the
upregulation of Id proteins through the activation of
mitogen-activated protein kinase (MAPK) signalling
and expression of EGR1 (early growth response 1)
and EGR2, resulting in the repression of E2A tran-
scriptional activity115–117. Notch 1 might also inhibit
E47 through Deltex in a CSL-independent manner118.
However, Notch 1 also exerts its leukaemogenic func-
tions in an E2A-independent manner, which indicates
the existence of parallel pathways. For example, murine
E2a–/– lymphomas accumulate Notch1 mutations and
depend on Notch 1 signalling, but neither of the Notch
target genes Ptrca or Hes1 (Hairy/enhancer of split)
could induce lymphomas in the absence of Notch
signalling119. Other target genes such as Nrarp (Notch-
regulated ankyrin-repeat protein) and Dtx1 (Deltex)
are known negative regulators of Notch and therefore
unlikely to contribute to transformation.
Notch 1 inhibits the activity of the tumour sup-
pressor p53, but the survival of thymic lymphomas
depends on Notch 1 even in the absence of p53
(REFS 97,119,120). The pro-apoptotic receptor NUR77
is required for the negative selection of T-cells and is
negatively regulated by Notch 1. Constitutive Notch
signalling might prevent TCR-induced apoptosis
and result in uncontrolled expansion and survival of
the thymocyte pool121–123. Moreover, lymphoblasts in
Notch-1-induced T-ALL are clonal, indicating that
additional oncogenic hits are required for leukaemo-
genesis. Accordingly, Notch 1 can collaborate with
MYC, E2A–PBX1 and dominant-negative Ikaros or
Ikaros-deficiency to induce T-cell acute leukaemia in
murine models109,124–126. A recent transposon-based
mutagenesis screen in mice indicated that Rasgrp1
(Ras guanyl-releasing protein 1), which is a gene that
activates Ras signalling, and Sox8 might cooperate
Figure 5 | Correlation between gene-expression profiles and stage of thymocyte
differentiation. Genomic aberrations can be correlated with arrested maturation
during thymocyte development. LYL1+ (leukaemia, lymphoid 1) cases (a) show an
expression profile indicating maturation arrest at the earliest double-negative stage
(DN). HOX11+ (b) and HOX11L2+ (c) cases develop to the early cortical double-positive
stage (DP), whereas T-cell acute lymphoblastic leukemia 1 (TAL1+) cases (d) are arrested at
a late cortical DP stage. Gene-expression profiling of MLL+ (mixed-lineage leukaemia)
cases (e) indicates commitment to the γδ lineage. As shown here the gene-expression
profiles that are characteristic of each stage of maturation arrest indicate at least five
multistep molecular pathways that can result in the transformation of T-cell progenitors
during development. The expression profiles of oncogenic transcription factors and/or
loss of tumour suppressors are very similar in HOX11+ and HOX11L2+ cases. HOX11+,
HOX11L2+ and TAL1+ cases show high levels of MYC expression and share the loss of
cyclin-dependent kinase inhibitor 2A (CDKN2A), which encodes the tumour suppressors
p16INK4a and p14ARF, whereas LYL1+ cases show high expression levels of MYCN and
frequently have deletions on chromosome arms 5q and 13q. Finally, the MLL+ subset of
T-ALL cases expresses high levels of HOXA9, HOXA10, HOXC6 and MEIS1 (myeloid
ectopic integration site 1), which differs from other T-ALL cases, but is similar to other
leukaemias that express MLL fusion proteins. Note that the unifying feature of all classes
of expression profiles is the upregulation of NOTCH1, which indicates that mutations in
NOTCH1 might have occurred already in haematopoietic stem cells and might be
required as a first step towards transformation. ATM, ataxia telangiectasia mutated; ISP,
immature single-positive; LIM, LIM-domain only.
354 | MAY 2006 | VOLUME 6
© 2006 Nature Publishing Group
with Notch1 in inducing T-cell lymphoma127. In the
same study, Runx2 was identified as another potential
collaborator with Notch1 activation in T-cell onco-
genesis. However, this study awaits independent con-
firmation that these additional transposon insertions
do indeed cause cooperative mutations. Whatever the
mechanism, Notch 1 activation is clearly a central fac-
tor in T-ALL pathogenesis, exerting its influence in at
least five parallel multistep molecular pathways that
lead to T-ALL, as discussed below6.
Multistep molecular pathways in T-ALL
Gene-expression profiling, using DNA microarrays,
has proved useful in establishing a more accurate clas-
sification of T-ALL subtypes, including those without
any karyotypic alterations14,128 (FIG. 5). A combination
of gene-analysis strategies has identified five important
multistep pathways that lead to T-ALL induction, each
of which is characterized by distinct cytogenetic abnor-
malities and differentiation arrest at specific stages of
normal T-cell development. Similar to all other human
cancers, T-ALL is the result of multiple somatic muta-
tions that occur within the malignant clone. The first
two of these pathways are defined by the overexpression
of either TAL1 or LYL1 in concert with either LMO1
or LMO2. Expression of the cyclin D3 oncoprotein is
associated with TAL1-induced transformation, whereas
cyclin D2 is overexpressed in LYL1-transformed leukae-
mias. In the third and fourth pathways, either HOX11
or a HOX11-related oncoprotein is overexpressed.
Finally, a fifth pathway involves the MLL–ENL fusion
protein, with a characteristic pattern of overexpression
of specific HOX genes. Although the precise order of
the molecular changes is unclear, three of these path-
ways also depend on biallelic deletions of the short
arm of chromosome 9, which eliminate both copies of
CDKN2A, which encodes the p16INK4A and p14ARF
In the LYL1 pathway, deletions of 5q and 13q indi-
cate contributions from the loss of unknown tumour-
suppressor genes. In addition, H2AX and ATM (ataxia
telangiectasia mutated) are closely linked genes on
human chromosome band 11q23. Approximately 20%
of T-ALL cases show deletion of the regions contain-
ing one or both of these genes, and such deletions are
preferential in the TAL1 and LYL1 subtypes of T-ALL.
Microarray data further allow the correlation of gene-
expression profiles with thymocyte differentiation of
T-ALL subtypes (FIG. 5). The ability to classify T-ALL
according to shared pathways of leukaemic transfor-
mation (based on the activation of oncogenic tran-
scription factors) has important clinical implications.
For example, activation of HOX11 is associated with a
significantly better prognosis than the expression of
either TAL1 or LYL1 (REFS 14,15).
Many of the above-mentioned molecular alterations
appear in combinations (FIG. 5) in T-ALL patients and
are associated with similar gene-expression profiles,
indicating that various mutations can cause leukaemia
by hyperactivating a limited set of genes. NOTCH1
serves as a unifying target in this model, as activating
NOTCH1 mutations have now been found in all of the
most common subtypes of T-ALL and in more than
50% of all paediatric T-ALL cases (FIGS 1,5). These find-
ings have opened the way for clinical trials of Notch-
pathway inhibitors in human T-ALL. However, to
understand the mechanisms of Notch-1-induced trans-
formation and to design new drugs that will allow the
targeting of transformation pathways simultaneously
at multiple sites, it will be necessary to identify other
oncogenes and tumour suppressors that cooperate with
NOTCH1 in T-ALL pathogenesis. Besides the murine
models, the zebrafish affords a useful vertebrate system
for dissecting the transformation pathways that lead to
T-ALL (BOX 1).
Implications for treatment
The high prevalence of NOTCH1 mutations in T-ALL
makes it an ideal target for pharmacological interven-
tion. In principle, Notch signalling could be inhibited
at several levels: ligand binding, endocytosis, prote-
olysis or transcriptional activity. So, recombinant
extracellular domains could function as competitive
inhibitors for Notch receptor–ligand interactions129,
and small-molecule inhibitors of proteolysis (S2 and
S3 cleavage steps) could be used to block ICN1 lib-
eration and nuclear translocation130, whereas domi-
nant-negative forms of MAML or CSL might decrease
the transcriptional activation of target genes87,103. In
practice, small-molecule inhibitors of the γ-secretase
complex (GSIs), which prevent ICN1 liberation
Box 1 | How are cooperating genes identifed in cancer?
Strategically designed matings of genetically engineered mice have been used
successfully to elucidate multistep pathways in T-cell transformation134. In such studies,
murine gene-knockout models provide essential information regarding the oncogenes
that are activated in leukaemia and lymphoma110,135,136. However, these knockout
strategies require prior knowledge of the genes that need to be inactivated — this
limitation can be overcome by using retroviral insertional mutagenesis screens to
uncover oncogenes. Recently, the Sleeping Beauty transposon system was used to
identify oncogenes and tumorigenic networks in mice127,137. Transposon insertional
screens have great potential because they can be designed to identify both oncogenes
and tumour suppressors, although tumour suppressors are rarely uncovered because of
the need for biallelic integration.
The zebrafish offers a powerful alternative vertebrate model system. Originally used
for the analysis of embryonic development, this model has since become established
in the study of human diseases, including cancer. Unbiased forward genetic analyses
with zebrafish models of cancer provide the means to identify novel genes in
tumorigenic pathways, as well as an unparalleled capacity for the in vivo analysis of
disease progression. A particular strength of the zebrafish cancer model, besides its
capacity for forward-genetic and chemical-modifier screens, is the opportunity that
it affords for direct observation of tumorigenic processes in vivo using fluorescent
technologies. The feasibility of modelling T-cell acute lymphoblastic leukaemia in
zebrafish was demonstrated with the MYC oncogene, proving that a genetic
predisposition to cancer can be stably acquired in this species138–140. The high degree
of genetic conservation between humans and zebrafish extends to Notch signalling,
as all of the important components of this pathway in humans have orthologues in
zebrafish (TABLE 2). A transgenic zebrafish model of Notch-induced T-cell acute
leukaemia, based on overexpression of green fluorescent protein (GFP) fusions to
human ICN1 (intracellular domain of Notch 1) or full-length Notch 1 with mutations in
the heterodimerization and PEST (polypeptide enriched in proline, glutamate, serine
and threonine) domains, would be ideal for genetic and chemical screens to identify
modifiers of the disease phenotype.
NATURE REVIEWS | CANCER
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© 2006 Nature Publishing Group
represent the most immediately promising therapeu-
tic approach in view of current capabilities for the
delivery of anticancer drugs. However, several prob-
lems need to be considered in designing successful
GSI treatment for T-ALL. First, GSIs are not specific
for Notch. Initially developed as drugs for Alzheimer
disease, these inhibitors also affect cleavage of
other transmembrane proteins, such as E-cadherin,
CD44, the epidermal-growth-factor receptor and the
amyloid-β A4 precursor protein131.
Interestingly, the most striking side effects of
GSIs administered to mice mimic the effects of loss
of Notch activity, especially in the lymphoid and
intestinal systems132. Weng et al. also reported that
several T-ALL cell lines with NOTCH1 mutations
were not responsive to inhibition of the γ-secretase
complex in vitro104. The authors speculated that this
might be due to long-term culturing of the cell lines,
which renders them independent of sustained Notch
signalling through the acquisition of other mutations.
Currently, the mechanism of resistance by T-ALL cell
lines to GSIs has not been defined. However, prom-
ising results have been achieved using GSIs to treat
autoimmune encephalomyelitis in a mouse model
of multiple sclerosis133. GSIs, similar to any molecu-
larly targeted agent, will probably be most successful
when used in combination with standard multi-agent
chemotherapy for T-ALL. In light of the specific gene-
expression profiles that are associated with individual
subtypes of T-ALL, it might be possible to tailor
therapeutic approaches to specific cases. For example,
T-ALLs that contain both NOTCH1 mutations and the
recently discovered NUP214–ABL1 fusion protein
could be candidates for combination treatment with
GSIs and imatinib (which is an inhibitor of tyrosine-
kinase activity). The development of pharmacological
inhibitors that specifically target other components of
the Notch pathway would permit more-flexible and
specific therapeutic strategies.
Conclusions and future perspectives
The transforming potential of Notch 1 can ultimately
be viewed as a reflection of its normal function in
T-cell development. Active Notch 1 drives pluripotent
bone-marrow cells towards a thymocyte fate and
expands the pool of immature T-lymphocytes. These
T-cell precursors seem especially susceptible to Notch-
1-induced transformation. NOTCH1 mutations have
been identified in immature thymocytes and even in
uncommitted bone-marrow progenitors, representing
all molecular subtypes of T-ALL. Because NOTCH1 is
also expressed in HSCs, it will be interesting to learn
whether Notch mutations in bone-marrow stem cells
establish a platform for further oncogenic hits and the
generation of leukaemic stem cells. Because NOTCH1
serves as a unifying target for transforming mutations
in T-ALL, combination therapy with currently avail-
able Notch inhibitors, such as GSIs, might improve
clinical outcome in specific subtypes of T-ALL. To
fully exploit the therapeutic opportunities afforded
by Notch 1, we will need to find more specific means
of inhibiting its activity and to identify the genes that
cooperate in the development of Notch-1-induced
T-ALL, using all available in vitro and in vivo systems,
including T-ALL cell cultures and both mammalian
and zebrafish models.
Table 2 | Conserved Notch-pathway components
DLL1, DLL3, DLL4,
Delta a–d, Delta-like 4, Jagged 1a,
Jagged 1b, Jagged 2, Serrate a
Notch1a, Notch1b, Notch2, Notch3
Mindbomb1, Mindbomb2, Neuralized-
like 1, Neuralized-like 2, Neuralized-
Lunatic Fringe, Manic Fringe, Radical
Furin a, Furin b
Apx1, Dsl1, Lag2Ligands
GlycosylasesLFNG, MFNG, RFNG Fringe Unknown
Aph1, Nicastrin, Presenilin 1,
Presenilin 2, Presenilin enhancer
Mastermind-like 1–3, Rbpsuh,
Deltex (6 members), Mint1a, Mint1b,
Mint2, Numb, Nrarpa, Nrarpb
ADAM, a disintegrin and metalloproteinase domain; DLL, Delta-like; DTX, Deltex; FUR, Furin; JAG, Jagged; LFNG, Lunatic Fringe;
MAML, Mastermind-like; MFNG, Manic Fringe; MIB, Mindbomb; MINT, MSX2-interacting nuclear target; NCSTN, nicastrin; NRARP,
Notch-regulated ankyrin-repeat protein ; POFUT1, O-fucosyltransferase 1; PSEN, Presenilin; PSNEN, Presenilin enhancer
homologue; RFNG, Radical Fringe; Su(H), suppressor of hairless.
356 | MAY 2006 | VOLUME 6
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We thank A. A. Ferrando and W. S. Pear for permission to
modify their original figures and J. Gilbert for editorial review.
C.G. is supported by the Lady Tata Memorial Trust. Research
in the Look and von Boehmer laboratories is supported by a
programme project grant from the National Cancer
Competing interests statement
The authors declare no competing financial interests.
The following terms in this article are linked online to:
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
ABL1 | CBF1 | cyclin D3 | EML1 | ENL | HOX11 | HOX11L2 |
Ikaros | LCK | LMO1 | LMO2 | LYL1 | MAML | MLL | MYC | Notch1 |
NUP214 | p53 | Ptcra | TAL1 | TAL2
National Cancer Institute: http://www.cancer.gov
acute lymphoblastic leukaemia | chronic myeloid leukaemia
Atlas of Genetics and Cytogenetics in Oncology and
Locus Link: http://www.ncbi.nlm.nih.gov/LocusLink
Access to this links box is available online.
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