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Regulation of glucocorticoid receptor steroid binding and trafficking by the hsp90/hsp70-based chaperone machinery: implications for clinical intervention

Leukemia volume 19, pages 710–712 (2005)Cite this article

This invited commentary is addressed in the paper by Tissing et al published in this issue of Leukemia.1 In this paper, the authors build upon previous studies2 showing hsp90 transcription is not related to glucocorticoid (GC) resistance in pediatric acute lymphoblastic leukemia (ALL). The authors postulate that GC resistance in pediatric ALL may result from altered expression of hsp90 per se, or from altered expression of a critical component of the hsp90/hsp70-based chaperone machinery that is involved in GC receptor (GR) maturation and nuclear translocation. The authors measure the transcripts from cells of matched GC-sensitive and GC-resistant patients, and further identify that the mRNA expression levels of hsp90 and hsp90/hsp70-based chaperone machinery co-chaperones are not correlated to GC resistance. Understanding the molecular mechanisms related to GC sensitivity/resistance in pediatric ALL is important for increasing treatment success for poor responders. The authors' findings are of further interest given that hsp90 inhibitors are being evaluated in clinical trials as antineoplastic agents in multiple cancer types including pediatric ALL, adult ALL, and chronic myelogenous leukemia.

GCs are an integral component of pediatric ALL treatment protocols, and the in vivo response to GCs has been identified as one of the strongest independent predictive factors for treatment outcome within the Berlin–Frankfurt–Münster (BFM) trial group.3 Patients who respond poorly to 7-day treatment of GC monotherapy have a significantly lower probability of 5-year event-free survival, and cells from patients with relapsed ALL are 75- to 300-fold more resistant to GCs compared to cells taken at the initial diagnosis.4, 5 An array of molecular mechanisms of GC resistance in ALL have been previously identified or proposed (reviewed by Tissing et al4). The identified mechanisms of resistance (ie decreased expression of GR and a GR mutation possessing low GC binding affinity) do not fully account for all GC-resistant ALL, thus leading to speculation of other potential mechanisms. Potential mechanisms of GC resistance include a decreased number of functional GR molecules in the cell; inhibition of GC-induced upregulation of GR expression; genetic mutations, polymorphic variations, or splice variants of the GR; altered post-translational modifications or protein–protein interactions (eg GR-hsp90 or GR-NF-κB); and alterations in the GC-mediated apoptosis cascade.4 Since inhibition of hsp90 would result in a perceived decrease in functional GR molecules as well as a number of the other proposed mechanisms of GC resistance, it is indeed a potential explanation.

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  1. Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, MI, USA

    P J M Murphy

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Murphy, P. Regulation of glucocorticoid receptor steroid binding and trafficking by the hsp90/hsp70-based chaperone machinery: implications for clinical intervention. Leukemia 19, 710–712 (2005). https://doi.org/10.1038/sj.leu.2403687

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