Despite the enormous advances that have been made in the
treatment of the plasma cell malignancy multiple myeloma (MM)
this disease remains most often fatal. RAS, a family of GTPase
genes, is frequently mutated in MM patients (20-45%). It has been
shown that RAS oncoproteins, next to their classical roles in stimulating
growth and survival, also have tumor suppressive effects.
These effects are partially mediated through the Ras-Association
Domain Family (RASSF), a group of 10 proteins and numerous
isoforms. These tumor suppressors are often silenced in cancer cells
due to methylation of the promotor. So far, however, no data about
RASSF proteins is available in MM. Here, we investigated the
expression and role of RASSF4 in MM.
Using gene expression profiling data of 2 independent patient cohorts,
we found that RASSF4 expression is significantly downregulated
in MM cells compared to healthy bone marrow plasma cells and that a
low expression at time of diagnosis associates with a bad prognosis. In
addition, treatment with the histone deacetylase inhibitor quisinostat
and/or the DNA methyltransferase inhibitor decitabine significantly
increased RASSF4 expression both in vitro and in vivo, thus indicating
that epigenetic modifications are involved in this silencing. Next, to
elucidate the biological role of RASSF4 in MM we used a conditional
lentiviral delivery system. Tree human myeloma cell lines (HMCL),
namely AMO1, JJN3 and the IL-6 dependent cell line XG7, were
transduced with either the empty pLenti 6.3 vector (control) or
pLenti6.3 huRASSF4. Overexpression of RASSF4 in the HMCL
revealed that RASSF4 has a strong negative effect on MM cell viability
and potently induces apoptosis. This induction of apoptosis was found
to be caspase-3 mediated. In addition, RASSF4 was found to inhibit the
clonogenic capacity of the HMCL. Mechanistically, immunofluorescence
stainingfor RASSF4 showed that RASSF4 is co-localized with the
centrosome. In addition, RASSF4 overexpression was found to
downregulate the expression of the anti-apoptotic protein Bcl-2.
In conclusion, we have identified RASSF4 as a target for epigenetic
silencing in MM and demonstrated its tumor suppressive function in
MM cells. Further insights into the molecular mechanisms of RASSF4
in MM will continue to be explored both in vitro and in vivo.
Originele taal-2English
Pagina's (van-tot)227-227
Aantal pagina's1
TijdschriftClinical Lymphoma & Myeloma
StatusPublished - 23 sep 2015
Evenement15th International Myeloma Workshop - Rome, Italy
Duur: 23 sep 201526 sep 2015


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