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Stress-induced resistance in multiple myeloma: the biological and clinical implications for treatment

donderdag, 12 januari, 2012 - 16:00
Campus: Brussels Health Campus
Faculteit: Medicine and Pharmacy
auditorium R. Vanden Driessche
Junsong Hu

Multiple myeloma (MM) is a fatal B-cell
malignancy characterized by the production of a
monoclonal paraprotein, hypercalcemia,
increased bone marrow (BM) angiogenesis,
destructive bone disease. Over the past decade,
progress in the treatment of MM has transformed
our therapeutic approaches and improves the
outcome of affected patients. However, MM still
remains incurable, and has a high rate of relapse
and drug resistance.

In this work, we identified two kinds of stresses
(one is environmental stress: the hypoxic niche in
the BM; the other is proteasome inhibition
induced endoplasmic reticulum stress) and their
roles in MM biology. Firstly, we discovered that
hypoxia is a key feature of the MM BM
microenvironment by using murine 5T33MM
model. Importantly, we further demonstrated
that the hypoxic niche in MM BM could be used as
a target for treatment of MM, and successfully
introduced hypoxia-activated treatment strategy
into leukemia for the first time. Secondly,
focusing on the effect of proteasome inhibition
(bortezomib) in MM, we demonstrated the
mechanism how bortezomib induces Mcl-1
expression via endoplasmic reticulum stress
signaling. The results provide the molecular basis
for better understanding the mechanism of
bortezomib-resistance in MM.

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