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Blood, 15 March 2002, Vol. 99, No. 6, pp. 1885-1893
PLENARY PAPER
Myeloid cell factor-1 is a critical survival factor for
multiple myeloma
Bin Zhang,
Ivana Gojo, and
Robert G. Fenton
From the Greenebaum Cancer Center, University of
Maryland Medical System, Baltimore, MD.
Multiple myeloma (MM) is characterized by the accumulation of
malignant plasma cells in the bone marrow caused primarily by failure
of normal homeostatic mechanisms to prevent the expansion of
postgerminal center plasma cells. We have examined the molecular mechanisms that promote the survival of MM cells and have identified a
key role for myeloid cell factor-1 (Mcl-1), an antiapoptotic member of
the Bcl-2 family. These experiments were initiated by the observation
that MM cells were exquisitely sensitive to culture in the presence of
actinomycin D: caspase activation occurred within 3 hours of treatment
and cells were not protected by interleukin-6, the main MM cell
growth and survival factor. Actinomycin D-induced apoptosis was
blocked by proteasome inhibitors, suggesting that a labile protein was
required for MM cell survival. Further analysis demonstrated that Mcl-1
was likely to be the labile factor governing MM cell survival. Mcl-1
protein levels decreased rapidly after culture in the presence of
actinomycin D in concordance with effector caspase activation, but
addition of proteasome inhibitors reversed the loss of Mcl-1 and
maintained cell viability. The levels of other antiapoptotic proteins,
including Bcl-2 and members of the inhibitors-of-apoptosis family, were
unaffected by these interventions. Furthermore, Mcl-1 antisense
oligonucleotides caused a rapid down-regulation of Mcl-1 protein levels
and the coincident induction of apoptosis, whereas overexpression of
Mcl-1 delayed actinomycin D-induced apoptosis with kinetics that
correlated with expression levels of Mcl-1. These data indicate that
Mcl-1 expression is required for the survival of MM cells and may
represent an important target for future therapeutics.

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