Glucocorticoid resistance: a persistent riddle

Comment on Tissing et al, page 1045

Resistance of ALL blasts to glucocorticoid therapy does not appear to be due to decreased up-regulation of receptor promoter or receptor transcripts.

We know a great deal about how glucocorticoid hormones act in normal tissues. Upon entry into cells, they bind to receptors that are then translocated to the nucleus. In the nucleus, the receptor-steroid complex binds to response elements on DNA, thereby affecting transcription of specific genes.

Glucocorticoids have been an important component of the treatment of acute lymphoblastic leukemia (ALL) for more than 50 years. Nevertheless, we are still in the dark regarding mechanisms affecting sensitivity and resistance to these drugs. Hypotheses have included differences in the following: receptor numbers, receptor polymorphisms, splice variants, receptor phosphorylation, glutathione levels, multidrug resistance, transcription factor complex components, apoptosis pathways, and induction of endonuclease activity.¹  Although each of these may affect corticosteroid activity, none adequately explains sensitivity and resistance.

In this issue of Blood, Tissing and colleagues investigated the in vitro expression of mRNA for glucocorticoid receptor promoters and glucocorticoid receptors in leukemic blasts at baseline and after exposure of these cells to prednisolone (see figure). In contrast to normal tissues, exposure of blasts to steroid resulted in up-regulation of receptor promoter and receptor mRNA. The percentage use of different promoters did not change before and after exposure. Finally, results were similar in cells that were resistant or sensitive to prednisolone-induced cell death in vitro.FIG1 

What do these data imply for further research? Promoter mRNA expression was reported in percentages of each subtype. Could sensitivity/resistance be related to quantitative amounts rather than qualitative distributions? Are we measuring the correct receptor? Gametchu²  has described membrane glucocorticoid receptors. In some in vitro studies, response to corticosteroids correlated more strongly with levels of membrane receptors than with cytoplasmic receptors. A prospective Pediatric Oncology Group study relating event-free survival in ALL to levels of membrane and total blast cell corticosteroid receptors awaits longer patient follow-up.

Robert Frost wrote: “We dance round in a ring and suppose, But the secret sits in the middle and knows.” The answers to mechanisms of action and resistance to corticosteroids remain a riddle. ▪