Cancer Research in Switzerland - Krebsliga Schweiz

tions in conjunction with microarrays, we determined the
epigenetic state of 26,500 genes in each cell type and
compared this with the respective expression patterns. A
bioinformatics analysis system was developed to compare
the different measurements in the different cell types.
Results of study
The DNA methylation profiles of the EC and ES cells
showed only subtle differences, indicating that changes in
DNA methylation might not be an early feature of promoters
in the transition from ES to EC cells. Histone modification
profiles were subsequently created and showed
greater plasticity. The chromatin state of the promoters
studied was also compared with the expression states of
the respective genes. A study of the differentiation of ES
cells into neurons revealed context­dependant cross­talk
between Polycomb­mediated histone methylation and
DNA methylation, leading us to the idea that Polycomb
targets might become methylated at a later stage in cancer
stem cell development. Promoters becoming methylated
in the differentiation to neurons are enriched for
pluripotency genes, which are unmethylated in both the
ES and the EC cell lines studied.
Project coordinator
Dr. Dirk Schübeler
Friedrich Miescher Institut für
biomedizinische Forschung (FMI)
Maulbeerstrasse 66
CH­4058 Basel
Phone +41 (0)61 697 82 69
Fax +41 (0)61 697 39 76
dirk@fmi.ch
Schwaller Jürg | PIM serine/threonine kinases as
potential therapeutic targets in human haematological
malignancies (OCS 01830­02­2006)
Malignant disorders of the haematopoietic system are often
associated with uncontrolled activity of proteins with
enzymatic activity of protein kinases. These kinases transfer
phosphate molecules on their substrates (on serine,
threonine or tyrosine residues) and hereby deliver a wide
variety of cellular signals. We showed previously that
most cases of acute and chronic leukaemias are associated
with overexpression of the constitutively active PIM serine/threonine
kinases (PIM1, PIM2) that are essential for
uncontrolled growth and survival of leukaemic cell lines
and primary blasts. The goals of this project were: 1) to
characterize novel small molecule PIM inhibitors; and
2) to better understand the molecular mechanisms underlying
the leukaemogenic activity of PIM kinases. Working
in close collaboration with structural chemists, we were
able to identify several small molecules that selectively interacted
and blocked PIM kinases. These PIM kinase inhibitors
also significantly reduced growth and survival of
leukaemic cell lines and primary blasts from patients.
We studied the role of PIM kinases in induction and maintenance
of the disease in a mouse leukaemia model. Our
experiments revealed that PIM1 (but not PIM2) has a so
far unknown function in regulation of cellular migration to
the bone marrow. PIM1 seems to functionally regulate the
CXCL12/CXCR4 chemokine ligand/receptor signal trans­
duction pathway. After binding the ligand, the CXCL12/
CXCR4 ligand/receptor complex gets internalized and activates
multiple signals that control cellular adhesion and
migration. A part of the molecules becomes degraded and
newly formed, but the majority of the receptor is “recycled”
to the cell surface.
We were able to show that PIM1 phosphorylates a distinct
amino acid residue (serine 339) located in the intracellular
tail of the CXCR4 receptor. Cells lacking PIM1 show reduced
“recycling” to the cell surface, resulting in lower
numbers of CXCR4 receptor molecules at the surface,
which is associated with reduced homing and migration of
haematopoietic stem cells to the bone marrow. Leukaemic
cells (cell lines or primary blasts) with elevated PIM1 levels
exhibit more CXCR4 molecules on the surface and
enhanced cellular adhesion and migration. Interestingly,
treatment of the cells with our novel PIM inhibitors significantly
reduced the number of surface CXCR4 molecules
and migration of leukaemic cells.
Our work not only revealed a previously unknown molecular
mechanism underlying the leukaemogenic activity of
PIM kinases but also opened up the possibility to modulate
adhesion and migration of normal and leukaemic
haematopoietic stem cells with small molecule PIM kinase
inhibitors. These observations have provided additional
rationale for PIM kinase inhibitors to enter first clinical trials.
Project coordinator
Prof. Dr. Jürg Schwaller
Forschungsgruppe Kinderleukämie
Departement Biomedizin
Universitätsspital Basel
Hebelstrasse 20
CH­4031 Basel
Phone +41 (0)61 265 35 04
Fax +41 (0)61 265 23 50
j.schwaller@unibas.ch
Skoda Radek C. | Pathogenesis of myeloproliferative
disorders (OCS 01742­08­2005)
Myeloproliferative disorders (MPD) are chronic blood diseases
characterized by overproduction of blood cell precursors
in the bone marrow. Patients with MPD bear an
increased risk (5–20 %) to develop an acute leukaemia after
a variable latency. Therefore, MPD is often considered
a „pre­leukaemia“. We found that in about 70–80 % of
MPD patients, the blood stem cells carry a mutation in the
gene “Janus kinase 2” (JAK2). JAK2 is an enzyme that
transmits signals coming from the outside into the cell and
the mutation (JAK2­V617) amplifies the growth­promoting
effect of these signals, so that more blood cells are
formed. The aim of our studies is to better understand
how the JAK2­V617F mutation causes MPD, with which
partner genes it collaborates in this process and what the
predisposing events are that can favour the acquisition of
MPD.
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