Dexamethasone resistance in B-cell precursor childhood acute lymphoblastic leukemia occurs downstream of ligand-induced nuclear translocation of the …
PS Bachmann, R Gorman, KL MacKenzie… - Blood, 2005 - ashpublications.org
PS Bachmann, R Gorman, KL MacKenzie, L Lutze-Mann, RB Lock
Blood, 2005•ashpublications.orgGlucocorticoids are among the most effective agents used in the treatment of childhood
acute lymphoblastic leukemia (ALL), and patient response to treatment is an important
determinant of long-term outcome. Despite its clinical significance, the molecular basis of
glucocorticoid resistance in lymphoid malignancies is still poorly understood. We have
recently developed a highly clinically relevant experimental model of childhood ALL, in
which primary childhood ALL biopsies were established as xenografts in nonobese …
acute lymphoblastic leukemia (ALL), and patient response to treatment is an important
determinant of long-term outcome. Despite its clinical significance, the molecular basis of
glucocorticoid resistance in lymphoid malignancies is still poorly understood. We have
recently developed a highly clinically relevant experimental model of childhood ALL, in
which primary childhood ALL biopsies were established as xenografts in nonobese …
Abstract
Glucocorticoids are among the most effective agents used in the treatment of childhood acute lymphoblastic leukemia (ALL), and patient response to treatment is an important determinant of long-term outcome. Despite its clinical significance, the molecular basis of glucocorticoid resistance in lymphoid malignancies is still poorly understood. We have recently developed a highly clinically relevant experimental model of childhood ALL, in which primary childhood ALL biopsies were established as xenografts in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. The in vivo and in vitro responses of a panel of these xenografts to the glucocorticoid, dexamethasone, reflected the outcome of the patients from whom they were derived. In this report we show that glucocorticoid resistance in B-cell precursor (BCP) ALL xenografts was not due to down-regulation of the glucocorticoid receptor (GR) nor to defective ligand binding of the GR. Moreover, dexamethasone-induced GR translocation from the cytoplasm to the nucleus was comparable in all xenografts. However, glucocorticoid resistance was associated with profoundly attenuated induction of the BH3-only proapoptotic protein, Bim, when xenograft cells were exposed to dexamethasone. These results show that dexamethasone resistance in BCP ALL xenografts occurs downstream of ligand-induced nuclear translocation of the GR, but upstream of Bim induction.
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