Cancer Research in Switzerland - Krebsliga Schweiz

Maiwald-Urosevic Mirjana | Role of versican in
the biology of Sézary cells (OCS 01934-08-2006)
Sézary syndrome (SS) belongs to cutaneous lymphomas,
a heterogeneous group of lymphatic malignancies characterized
by red and scaly skin, lymph node enlargement
and the presence of atypical tumour lymphocytes, called
Sézary cells (SCs) in peripheral blood. In contrast to other
skin lymphomas with a T-cell phenotype, SS has an unfavourable
prognosis. The exact mechanisms underlying accumulation
of malignant SCs in the skin and/or enabling
their circulation in peripheral blood are still poorly defined.
Accordingly, the various treatments for SS are generally
disappointing, reflecting the need for new targets.
SCs appear to lack regulatory activity governing their response
to chemokines, which might potentate their homing
to the skin.
By using high-throughput gene expression profiling of SCs
obtained from peripheral blood of patients, we could
identify a highly overexpressed gene, termed versican.
Versican is one of the major components of the extracellular
matrix and is able to bind various chemokines, thus
influencing the cellular response to chemokines and
changing the migratory behaviour of lymphoid cells.
Moreover, overexpression of versican (or its different isoforms)
appears to be responsible for the changes in the
susceptibility of tumour cells to apoptosis.
The results obtained in this project provide new information
that can be used in the development of treatment
strategies targeting migratory behaviour of lymphoid tumour
cells. This could be of importance not only in skin
lymphomas but also in other T-cell malignancies with possible
blood involvement.
Project coordinator
PD Dr. Mirjana Maiwald-Urosevic
Dermatologische Klinik
UniversitätsSpital Zürich
Gloriastrasse 31
CH-8091 Zürich
Phone +41 (0)44 255 11 11
mirjana.maiwald@usz.ch
Matthes Thomas | Analysis of transcription factors
PU.1 and GATA-1 functions in myelodysplastic
syndromes, in acute myeloid leukemia and in leukemia
stem cells (OCS 01781-08-2005)
Transcription factors are intracytoplasmic proteins that
regulate the normal cell differentiation from undifferentiated
omnipotent stem cells to fully mature end-differentiated
cells with specialized functions in different organs. In
the haematopoietic system, they orchestrate the differentiation
into the various different red and white blood cells
that circulate in the peripheral blood and populate the
various lymphoid organs of the body. They also play a role
in acute myeloid leukaemia (AML), in which this normal
differentiation program is blocked, as well as in myelodysplastic
syndromes (MDS), preleukaemic states in which
transcription factor expression is dysregulated.
Aim
To study the function of two particular transcription factors,
PU.1, the key regulator of myelopoiesis, and GATA-1,
the key regulator of erythropoiesis, in normal haematopoietic
differentiation, in AML and in MDS.
Methods
We used lentivectors, which code for PU.1 or GATA-1, to
transduce normal stem cells, primary blast cells from patients
with AML, and AML cell lines, and from patients
with MDS. In in vitro cultures we analyzed the effect of
overexpressed PU.1 or GATA-1 on the differentiation and
proliferation potential of the transduced cells, on their
phenotype and on their resistance to apoptotic stimuli.
Results
Transduction of cells with the two lentivectors led to overexpression
of mRNA and protein of the corresponding
transcription factors. After several days of culture, blasts
transduced with PU.1 showed myelomonocytic differentiation
and phenotypic changes compatible with restored
blast differentiation. These effects were similar to the effects
observed by adding all-trans retinoic acid (ATRA) to
the cell cultures, a treatment currently used in the clinics
in a subtype of AML. At later time points cells showed
morphologic changes typical of macrophages, and increased
apoptosis, characteristic of end-differentiated
cells. The observed effects were dose-dependent and occurred
only when PU.1 levels were above a certain threshold.
Blast cells transduced with GATA-1 did not show any
of the effects observed in PU.1 transduced cells, although
GATA-1 protein levels were increased.
Conclusion
Our results show that artificially induced changes in transcription
factor levels can influence the destiny of leukaemic
blast cells by overcoming the differentiation block
typical of these cells and restoring their normal differentiation
program. Targeting PU.1 or one of the other known
molecules in the PU.1 signal transduction pathway in AML
could therefore constitute an interesting alternative approach
for the treatment of this still incurable disease.
Project coordinator
Dr Thomas Matthes
Service d’hématologie
Département de médicine interne
Hôpitaux universitaires de Genève (HUG)
6, rue Gabrielle-Perret-Gentil
CH-1211 Genève 4
Phone +41 (0)21 372 39 30
Fax +41 (0)21 372 72 88
thomas.matthes@hcuge.ch
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