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Gene regulation by lentiviral vectors and epigenetic modifications in multiple myeloma

Tuesday, 21 December, 2010 - 17:00
Campus: Brussels Health Campus
Faculty: Medicine and Pharmacy
auditorium P. Brouwer
Tomas Bos
phd defence

Multiple myeloma (MM) is a devastating cancer
characterized by the uncontrolled proliferation of
monoclonal plasma cells in the bone marrow.
There, the tumor cells are nurtured and
stimulated by the microenvironment to
proliferate. In this thesis, we focused on two
novel techniques to study the interactions
between tumor cells and the microenvironment.
Lentiviral vectors have been described as ideal
shuttles to stably incorporate foreign DNA into
target cells. In two projects, we aimed at
optimizing the expression of multiple proteins
from one single lentiviral vector. First, we pushed
the lentiviral vector system by inserting
increasing-sized transgenes into its 3’LTR, thus
generating large double copy vectors (DCV).
These DCV proved to be functional regardless the
size and nature of the insert, but demonstrated a
size-dependent decline in transduction efficiency.
In the second project, we focused on the
bicistronic lentiviral vectors. We demonstrated
that the nature of this linker was responsible for
the transcriptional level of the transgenes and
showed that a construct containing the 2A-selfcleaving
linker was superior over identical
constructs containing the IRES and SIRES linkers.
In the second part of this thesis, we showed that
the expression of the proapoptotic Bim-gene was
directly regulated by IGF-1, one of the major
growth factors involved in MM. By further
dissecting the mechanisms involved in the
regulation, we demonstrated that IGF-1 directly
influences the post-translational histone marks at
both the Bim- and FoxO3A-promoter. Finally, we
showed that Bim-depletion in MM resulted in
resistance to drugs commonly used to treat MM.