Physiological and pathogenic interleukin-7-receptor (IL7R)-induced signaling provokes
glucocorticoid resistance in a subset of patients with pediatric T-cell
acute lymphoblastic leukemia (
T-ALL). Activation of downstream STAT5 has been suggested to cause
steroid resistance through upregulation of anti-apoptotic BCL2, one of its downstream target genes. Here we demonstrate that isolated STAT5 signaling in various
T-ALL cell models is insufficient to raise cellular
steroid resistance despite upregulation of BCL2 and BCL-XL. Upregulation of anti-apoptotic BCL2 and BCLXL in STAT5-activated
T-ALL cells requires
steroid-induced activation of NR3C1. For the BCLXL locus, this is facilitated by a concerted action of NR3C1 and activated STAT5 molecules at two STAT5 regulatory sites, whereas for the BCL2 locus this is facilitated by binding of NR3C1 at a STAT5 binding motif. In contrast, STAT5 occupancy at
glucocorticoid response elements does not affect the expression of NR3C1 target genes. Strong upregulation of BIM, a NR3C1 pro-apoptotic target gene, upon
prednisolone treatment can counterbalance NR3C1/STAT5-induced BCL2 and BCL-XL expression downstream of IL7- induced or pathogenic IL7R signaling. This explains why isolated STAT5 activation does not directly impair the
steroid response. Our study suggests that STAT5 activation only contributes to
steroid resistance in combination with cellular defects or alternative signaling routes that disable the pro-apoptotic and
steroid-induced BIM response.