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A mechanism of resistance to glucocorticoids in multiple myeloma: transient
expression of a truncated glucocorticoid receptor mRNA
PA Moalli, S Pillay, D Weiner, R Leikin and ST Rosen
Department of Medicine, Northwestern University, Chicago, IL.
Despite their widespread use, little is known of either the mechanism of
action of glucocorticoids in the treatment of multiple myeloma or why
patients ultimately become resistant to their therapeutic effects. Here, we
address these issues by examining the direct effects of the glucocorticoid
dexamethasone (DEX) on a hormone-sensitive clone (MM.1S) of a human
multiple myeloma line and compare them with those of its hormone-resistant
counterpart (MM.1R). MM.1S expresses approximately 50,000 glucocorticoid
receptors (GR) per cell, the full-length 7.1-kb GR mRNA at high levels, and
is lysed by DEX. DEX-induced cytolysis is effectively blocked by the
glucocorticoid antagonist, RU 486, indicating the specificity of this
response for the GR. In contrast to MM.1S, MM.1R is not lysed by hormone,
has little hormone-binding activity, and expresses the 7.1-kb GR mRNA at
low levels. Interestingly, we have found that two distinct phenotypes
emerge from MM.1R with increasing periods of growth in culture. The first
or "early" form, MM.1Re, expresses high levels of a variant GR mRNA of 5.5
kb that has a deletion in its 3' end. With further growth in the presence
or absence of selective media, the expression of this transcript is
repressed, resulting in the second or "late" phenotype characteristic of
MM.1RL. No discernible differences in the organization of the genomic GR
sequence in DEX-sensitive and -resistant cells were detectable by Southern
analysis, suggesting that no gross deletions, rearrangements, or allelic
variations in the genomic sequence account for the resistant phenotypes of
MM.1R.
Volume 79,
Issue 1,
pp. 213-222,
01/01/1992
Copyright © 1992 by The American Society of Hematology
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