Identification of glucocorticoid-response genes in children with acute lymphoblastic leukemia

Abstract

The ability of glucocorticoids (GCs) to kill lymphoid cells led to their inclusion in essentially all chemotherapy protocols for lymphoid malignancies, particularly childhood acute lymphoblastic leukemia (ALL). GCs mediate apoptosis via their cognate receptor and subsequent alterations in gene expression. Previous investigations, including expression profiling studies with subgenome microarrays in model systems, have led to a number of attractive, but conflicting, hypotheses that have never been tested in a clinical setting. Here, we present a comparative whole-genome expression profiling approach using lymphoblasts (purified at 3 time points) from 13 GC-sensitive children undergoing therapy for ALL. For comparisons, expression profiles were generated from an adult patient with ALL, peripheral blood lymphocytes from GCexposed healthy donors, GC-sensitive and -resistant ALL cell lines, and mouse thymocytes treated with GCs in vivo and in vitro. This generated an essentially complete list of GC-regulated candidate genes in clinical settings and experimental systems, allowing immediate analysis of any gene for its potential significance to GCinduced apoptosis. Our analysis argued against most of the model-based hypotheses and instead identified a small number of novel candidate genes, including PFKFB2, a key regulator of glucose metabolism; ZBTB16, a putative transcription factor; and SNF1LK, a protein kinase implicated in cell-cycle regulation. (Blood.

Tissue-specific induction of ADAMTS2 in monocytes and macrophages by glucocorticoids

“…1, 2). Although the impact of GC on global gene expression has been studied [34][35][36][37], this is a novel finding not reported in the literature before. This effect may have been overlooked because it takes 48 h to reach its full magnitude, with a plateau at 120 h (Fig.…”

Levels of glucocorticoid receptor and its ligand determine sensitivity and kinetics of glucocorticoid-induced leukemia apoptosis

“…GC resistance in in vitro models has been shown to result from mutations in the GR gene or lack of GR auto-induction 3 a phenomenon seen in several GC-sensitive ALL cell lines 2,4 and some children with T-ALL. 5 GR mutations are however, rarely seen in samples from patients at relapse. 6 Whether basal GR levels and/or GR auto-induction might contribute to GC resistance in patients is controversial.…”

“…To this end, identically prepared protein lysates from doxycycline-treated 1B11 cells, dexamethasone-treated CEM-C7H2 cells, and malignant lymphoblasts from children with precursor B-or T-ALL (prior to and after initiation of systemic GC monotherapy) 5 were size-separated on the same SDS-PAGE and immuno-blotted with antibodies against GR and a-tubulin as loading control (Supplementary Figure S3). The signals obtained with the two antibodies were quantified and Letters to the Editor related to each other thereby deriving a-tubulin normalized GR levels.…”

Effect of ligand-activated estrogen receptor β on lymphoma growth in vitro and in vivo

“…However, gender differences may also operate through alternative mechanisms as ER expression is not found in all leukemias. 36 Considering E 2 being an efficient agonist for both ERa and ERb, E 2 had a surprisingly small antiproliferative effect on EG7 murine lymphoma growth in vivo and in vitro compared with DPN or KB9520. This could possibly be explained by the presence of small, but by immunocytochemistry undetectable, levels of ERa in these cells that in the presence of E 2 counteracts ERb activity.…”