PMID- 17077285
OWN - NLM
STAT- MEDLINE
DCOM- 20070101
LR  - 20220129
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 20
IP  - 14
DP  - 2006 Dec
TI  - Glucocorticoid resistance in two key models of acute lymphoblastic leukemia 
      occurs at the level of the glucocorticoid receptor.
PG  - 2600-2
AB  - Glucocorticoids (GCs) specifically induce apoptosis in malignant lymphoblasts and 
      are thus pivotal in the treatment of acute lymphoblastic leukemia (ALL). However, 
      GC-resistance is a therapeutic problem with an unclear molecular mechanism. We 
      generated approximately 70 GC-resistant sublines from a GC-sensitive B- and a 
      T-ALL cell line and investigated their mechanisms of resistance. In response to 
      GCs, all GC-resistant subclones analyzed by real-time polymerase chain reaction 
      (PCR) showed a deficient up-regulation of the GC-receptor (GR) and its downstream 
      target, GC-induced leucine zipper. This deficiency in GR up-regulation was 
      confirmed by Western blotting and on retroviral overexpression of GR in resistant 
      subclones GC-sensitivity was restored. All GC-resistant subclones were screened 
      for GR mutations using denaturing high-pressure liquid chromatography (DHPLC), 
      DNA-fingerprinting, and fluorescence in situ hybridization (FISH). Among the 
      identified mutations were some previously not associated with GC resistance: 
      A484D, P515H, L756N, Y663H, L680P, and R714W. This approach revealed three 
      genotypes, complete loss of functional GR in the mismatch repair deficient T-ALL 
      model, apparently normal GR genes in B-ALLs, and heterozygosity in both. In the 
      first genotype, deficiency in GR up-regulation was fully explained by mutational 
      events, in the second by a putative regulatory defect, and in the third by a 
      combination thereof. In all instances, GC-resistance occurred at the level of the 
      GR in both models.
FAU - Schmidt, Stefan
AU  - Schmidt S
AD  - Tyrolean Cancer Research Institute, Innrain 66, A-6020 Innsbruck, Austria. 
      stefan.schmidt@i-med.ac.at
FAU - Irving, Julie A E
AU  - Irving JA
FAU - Minto, Lynne
AU  - Minto L
FAU - Matheson, Elizabeth
AU  - Matheson E
FAU - Nicholson, Lindsay
AU  - Nicholson L
FAU - Ploner, Andreas
AU  - Ploner A
FAU - Parson, Walther
AU  - Parson W
FAU - Kofler, Anita
AU  - Kofler A
FAU - Amort, Melanie
AU  - Amort M
FAU - Erdel, Martin
AU  - Erdel M
FAU - Hall, Andy
AU  - Hall A
FAU - Kofler, Reinhard
AU  - Kofler R
LA  - eng
GR  - P 18571/FWF_/Austrian Science Fund FWF/Austria
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20061031
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (Glucocorticoids)
RN  - 0 (Receptors, Glucocorticoid)
RN  - 0 (TSC22D3 protein, human)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Cell Line, Tumor
MH  - DNA Mismatch Repair
MH  - *Drug Resistance, Neoplasm/genetics
MH  - Glucocorticoids/metabolism/*therapeutic use
MH  - Humans
MH  - Mutation
MH  - Precursor Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy
MH  - Receptors, Glucocorticoid/genetics/*metabolism
MH  - Transcription Factors/metabolism
EDAT- 2006/11/02 09:00
MHDA- 2007/01/02 09:00
CRDT- 2006/11/02 09:00
PHST- 2006/11/02 09:00 [pubmed]
PHST- 2007/01/02 09:00 [medline]
PHST- 2006/11/02 09:00 [entrez]
AID - fj.06-6214fje [pii]
AID - 10.1096/fj.06-6214fje [doi]
PST - ppublish
SO  - FASEB J. 2006 Dec;20(14):2600-2. doi: 10.1096/fj.06-6214fje. Epub 2006 Oct 31.