Cancer Research in Switzerland - Krebsliga Schweiz

of Notch1. However, simultaneous inactivation of both
Notch1 and Notch2 in the skin differed from skin specific
Notch1 mutant mice. Simultaneous loss of both receptors
in the skin induced the development of a severe form of
atopic dermatitis (also known as eczema), which is associated
with massive inflammation within 4 weeks. Likewise,
analysis of patients with atopic dermatitis but no other
skin diseases (such as psoriasis) showed also a marked reduction
of Notch receptor expression in the skin. Loss of
Notch in keratinocytes induces the production of thymic
stromal lymphopoietin (TSLP), a cytokine deeply implicated
in the pathogenesis of AD. The AD­like associated
inflammation is accompanied by a lethal myeloproliferative
disorder (MPD) characterized by an increase in immature
myeloid populations in the bone marrow and spleen.
Transplantation studies revealed that the MPD is cell nonautonomous
and caused by dramatic microenvironmental
alterations. Genetic studies demonstrated that the increased
G­CSF concentration in the serum of the Notch
mutant mice is responsible for the MPD. Our study demonstrates
a critical role for both Notch receptors in repressing
TSLP production in keratinocytes, thereby maintaining
integrity of the skin and the haematopoietic system.
Project coordinator
Prof. Dr Freddy Radtke
Institut suisse de recherche expérimentale
sur le cancer (ISREC)
Faculté des sciences de la vie
EPF de Lausanne (EPFL)
Station 19
CH­1015 Lausanne
Phone +41 (0)21 693 07 71
freddy.radtke@epfl.ch
Radtke Freddy | The role of Notch1 signaling in acute
lymphoblastic T cell leukaemia (T-ALL)
(KLS 01840­02­2006)
T cells are haematopoietic cells that are part of our immune
system to protect us against foreign invaders. T cell
development occurs in the thymus, where unspecified
bone marrow progenitors differentiate and mature within
a period of approximately three weeks into functional
T cells. This differentiation process is regulated and driven
by several ligand­receptor interactions that induce a complex
transcriptional network that assures proper growth
and differentiation of functional T cells. Deregulation of
these processes, combined with the acquisition of genetic
alterations, is causative of leukaemogenesis. T cell acute
lymphoblastic leukaemia (T­ALL) is an aggressive malignancy
that originates in the thymus. The disease represents
15 % of paediatric and 25 % of adult acute lymphoblastic
leukaemia (ALL) cases. The general treatment
consists of multi­agent chemotherapy, which results in an
overall survival rate of 70 % for children and 30–40 % for
adults. Although the cure rates appear to be relatively
high, 30 % of children and 60 % of adult patients relapse
and have a poor prognosis. It is therefore important to
better understand the molecular mechanisms contributing
to malignant T cell growth. The Notch1 receptor is
part of a family of transmembrane bound receptors that
mediate signals from the outside to the inside of a cell and
thereby influence development and growth. Physiological
Notch1 signalling in the blood system and in particular in
the thymus is essential for generating T cells. However,
too much signalling causes malignant growth. More than
50 % of all T­ALL patients have small changes within the
receptor (called point mutations); this causes the receptor
to signal too strong, too long and at inappropriate stages
of development and thus causes leukaemia.
We generated a Notch driven leukaemic mouse model
that recapitulates the human disease and showed that
Notch signalling is not only required for the development
of the disease but continuous signalling is also essential
for the maintenance of the disease. Thus Notch1 is a master
regulator for malignant T cell growth.
Further, we investigated the role of the transcription factor
Hes1 for normal and malignant T cell growth and development.
Hes1 is one of numerous transcription factors
that become activated when Notch1 signals. Our studies
showed that under physiological conditions Hes1 is important
for normal T cell development. In its absence only
very few T cells are able to develop. More importantly, we
showed that Hes1 is essential for the development and
maintenance of Notch1 driven leukaemia in our mouse
model. Most importantly, reducing Hes1 protein levels
in established patient­derived human T­ALL samples
resulted in growth retardation and cell death, strongly
suggesting that the important role for Hes1 might not be
restricted to T­ALL mouse models but could also apply
to the human disease. Thus, our studies identified Hes1 as
a main mediator of Notch1 signalling in the physiological
and leukaemic situation and highlight it as a potential
therapeutic target to fight against malignant growth of
T­ALL.
Project coordinator
Prof. Dr Freddy Radtke
Institut suisse de recherche expérimentale
sur le cancer (ISREC)
Faculté des sciences de la vie
EPF de Lausanne (EPFL)
Station 19
CH­1015 Lausanne
Phone +41 (0)21 693 07 71
freddy.radtke@epfl.ch
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