PMID- 35734930
OWN - NLM
STAT- MEDLINE
DCOM- 20230302
LR  - 20230310
IS  - 1592-8721 (Electronic)
IS  - 0390-6078 (Print)
IS  - 0390-6078 (Linking)
VI  - 108
IP  - 3
DP  - 2023 Mar 1
TI  - STAT5 does not drive steroid resistance in T-cell acute lymphoblastic leukemia 
      despite the activation of BCL2 and BCLXL following glucocorticoid treatment.
PG  - 732-746
LID - 10.3324/haematol.2021.280405 [doi]
AB  - 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.
FAU - Van der Zwet, Jordy C G
AU  - Van der Zwet JCG
AD  - Princess Maxima Center for Pediatric Oncology, Utrecht.
FAU - Cordo', Valentina
AU  - Cordo' V
AD  - Princess Maxima Center for Pediatric Oncology, Utrecht.
FAU - Buijs-Gladdines, Jessica G C A M
AU  - Buijs-Gladdines JGCAM
AD  - Princess Maxima Center for Pediatric Oncology, Utrecht.
FAU - Hagelaar, Rico
AU  - Hagelaar R
AD  - Princess Maxima Center for Pediatric Oncology, Utrecht.
FAU - Smits, Willem K
AU  - Smits WK
AD  - Princess Maxima Center for Pediatric Oncology, Utrecht.
FAU - Vroegindeweij, Eric
AU  - Vroegindeweij E
AD  - Princess Maxima Center for Pediatric Oncology, Utrecht.
FAU - Graus, Laura T M
AU  - Graus LTM
AD  - Princess Maxima Center for Pediatric Oncology, Utrecht.
FAU - Poort, Vera
AU  - Poort V
AD  - Princess Maxima Center for Pediatric Oncology, Utrecht.
FAU - Nulle, Marloes
AU  - Nulle M
AD  - Princess Maxima Center for Pediatric Oncology, Utrecht.
FAU - Pieters, Rob
AU  - Pieters R
AD  - Princess Maxima Center for Pediatric Oncology, Utrecht.
FAU - Meijerink, Jules P P
AU  - Meijerink JPP
AD  - Princess Maxima Center for Pediatric Oncology, Utrecht. 
      j.meijerink@prinsesmaximacentrum.nl.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230301
PL  - Italy
TA  - Haematologica
JT  - Haematologica
JID - 0417435
RN  - 0 (Glucocorticoids)
RN  - 0 (STAT5 Transcription Factor)
RN  - 0 (Steroids)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (BCL2 protein, human)
SB  - IM
CIN - Haematologica. 2023 Mar 01;108(3):670-672. PMID: 35734928
MH  - Humans
MH  - Child
MH  - *Glucocorticoids/pharmacology
MH  - *Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug 
      therapy/genetics/metabolism
MH  - STAT5 Transcription Factor/metabolism
MH  - Steroids
MH  - Proto-Oncogene Proteins c-bcl-2/genetics/metabolism
MH  - T-Lymphocytes/metabolism
MH  - Apoptosis
PMC - PMC9973477
EDAT- 2022/06/24 06:00
MHDA- 2023/03/03 06:00
PMCR- 2022/06/23
CRDT- 2022/06/23 04:01
PHST- 2021/11/23 00:00 [received]
PHST- 2022/06/24 06:00 [pubmed]
PHST- 2023/03/03 06:00 [medline]
PHST- 2022/06/23 04:01 [entrez]
PHST- 2022/06/23 00:00 [pmc-release]
AID - 10.3324/haematol.2021.280405 [doi]
PST - epublish
SO  - Haematologica. 2023 Mar 1;108(3):732-746. doi: 10.3324/haematol.2021.280405.