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Blood, 1 November 2000, Vol. 96, No. 9, pp. 3175-3180
NEOPLASIA
Heterogeneity in therapeutic response of genetically altered
myeloma cell lines to interleukin 6, dexamethasone, doxorubicin,
and melphalan
Matt Rowley,
Pocheng Liu, and
Brian Van
Ness
From the Graduate Program in Molecular, Cellular,
Developmental Biology, and Genetics; the Department of Laboratory
Medicine and Pathology; the Department of Genetics, Cell, and
Developmental Biology; and The Cancer Center, University of Minnesota,
Minneapolis, MN.
Because there is no known genetic abnormality common to all
patients with myeloma, it is important to understand how genetic heterogeneity may lead to differences in signal transduction, cell
cycle, and response to therapy. Model cell lines have been used to
study the effect that mutations in p53 and ras
can have on growth properties and responses of myeloma cells. The U266 cell line has a single mutant p53 allele. Stable expression
of wild-type (wt) p53 in U266 cells results in a
significant suppression of interleukin (IL)-6 gene expression and in
the concomitant suppression of cell growth that could be restored by
the addition of exogenous IL-6. Expression of wt p53 also
leads to cell cycle arrest and protection from doxorubicin (Dox)- and
melphalan (Mel)-induced apoptosis. The addition of IL-6 resulted in
cell cycle progression and blocked p53-mediated protection from
apoptosis. ANBL6 is an IL-6-dependent cell line that is sensitive to
dexamethasone (Dex), Dox, and Mel. IL-6 is able to protect ANBL6 cells
from Dex- and Mel- but not Dox-induced apoptosis. To study the effect
of an activating mutation in ras, the ANBL6 cell line
transfected with either a constitutively activated N- or
K-ras gene was used. Both N-ras12 and
K-ras12 genes were able to protect ANBL6 cells from apoptosis induced by Dex, Dox, and Mel. These data show that changes in
ras or p53 can alter the myeloma cell response
to IL-6 and demonstrate that the genetic background can alter
therapeutic responses.
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