Glucocorticoid Resistance in Childhood Leukemia

Abstract

Glucocorticoids (GC) are being used in the treatment of childhood leukemia for several decades, most successfully in newly diagnosed acute lymphoblastic leukemia (ALL). However, GC resistance is seen in 10-30% of untreated ALL patients, and is much more frequent in relapsed ALL and in acute nonlymphoblastic leukemia (ANLL). Sensitivity or resistance to GC can be measured using a cell culture drug resistance assay. For this purpose, we use the colorimetric methyl-thiazol-tetrazolium (MTT) assay. We have shown that GC resistance in childhood leukemia is related to clinical and cell biological features, and to the clinical outcome after multi-drug chemotherapy. These results are summarized in this review. In addition, we describe the apoptotic 'cell-lysis pathway' by which GC exert their antileukemic activity. This description provides a model to discuss the mechanisms of GC resistance, and to summarize the relevant literature. Possible levels of resistance relate to the diffusion of GC through the cell membrane, binding to the GC receptor (GCR), activation of the GC-GCR complex, translocation of the complex into the nucleus, binding to DNA, endonuclease-mediated DNA fragmentation, and DNA repair. A low number of GCR has been shown to be the cause of resistance in some children with ALL. However, GC resistance is likely to be caused at the post-receptor level in most leukemias. Unfortunately, there is still a lack of knowledge relating to the clinical relevance of mechanisms of GC resistance at the post-receptor level. Studies on the mechanisms of GC resistance other than those directly related to the GCR should be initiated, especially if patient material is used, as the results might indicate ways to circumvent or modulate GC resistance. A further increase in our knowledge regarding the relation between GC resistance and patient and cell biological features, the clinical relevance of GC resistance, and the mechanisms of GC resistance in leukemia patients, may contribute to further improvement in the results of GC therapy in leukemia.

The role of AP-1 in glucocorticoid resistance in leukaemia

“…[13][14][15] Furthermore, reduced affinity of GR for its ligand, defective translocation of GR across the nuclear membrane and binding of the GR to the GRE are also not thought to be of major importance in glucocorticoid resistance in leukaemia. 1 A number of other possible mechanisms of resistance to glucocorticoids may occur downstream of the action of the receptor. The inhibition of poly-ADP-ribose-polymerase (PARP) by benzamide, 3-aminobenzamide and nicotinamide has been shown to enhance GC induced apoptosis.…”

“…In ALL approximately 20% of patients are resistant to glucocorticoids at time of presentation but in those patients that relapse up to 80% are resistant. 1,2 The actions of glucocorticoids are mediated through specific intracellular glucocorticoid receptors (GR) found in almost all mammalian cells. The human GR is an acidic phosphoprotein with a molecular weight of 97 kDa.…”

mRNA expression levels of (co)chaperone molecules of the glucocorticoid receptor are not involved in glucocorticoid resistance in pediatric ALL

“…Using dexamethasone binding assays, it was shown that decreased binding of dexamethasone was related to GC resistance in childhood ALL. Although this finding was regarded to be due to a lower expression level of the GR, 32 it may alternatively be related to a reduced rate in complex maturation due to defects in one of these molecules other than just the expression level of these molecules. However, to study the formation of the GR-(co)chaperone complex will be very difficult when using patient material, as the different stages of this complex will pass quickly.…”

Unsupervised proteome analysis of human leukaemia cells identifies the Valosin-containing protein as a putative marker for glucocorticoid resistance

“…Several studies with respect to specific targets like the glucocorticoid receptor (GR) and its splice variants, to proteins involved in the activation process of the GR and genetic variants of drug resistance genes or of the GR itself did not show any correlation between the results and the GC resistance. [21][22][23][24][25][26][27][28][29][30][31] In contrast to many proteome screening studies in human tissues, the advantage of the current study is that proteins were isolated from purified leukaemic cells that had all been processed and stored in the same manner. The minimum percentage of leukaemic blasts in the bone marrow of patients investigated was 77% before gradient centrifugation.…”