Genetic alterations in glucocorticoid signaling pathway components are associated with adverse prognosis in children with relapsed ETV6/RUNX1-positive acute lymphoblastic leukemia.
The ETV6/RUNX1 gene fusion defines the largest genetic subgroup of childhood ALL with overall rapid treatment response. However, up to 15% of cases relapse. Because an impaired glucocorticoid pathway is implicated in disease recurrence we studied the impact of genetic alterations by SNP array analysis in 31 relapsed cases. In 58% of samples, we found deletions in various glucocorticoid signaling pathway-associated genes, but only NR3C1 and ETV6 deletions prevailed in minimal residual disease poor responding and subsequently relapsing cases (p<0.05). To prove the necessity of a functional glucocorticoid receptor, we reconstituted wild-type NR3C1 expression in mutant, glucocorticoid-resistant REH cells and studied the glucocorticoid response in vitro and in a xenograft mouse model. While these results prove that glucocorticoid receptor defects are crucial for glucocorticoid resistance in an experimental setting, they do not address the essential clinical situation where glucocorticoid resistance at relapse is rather part of a global drug resistance.
a Children's Cancer Research Institute, St. Anna Kinderkrebsforschung , Vienna , Austria .
Reinhard
R
Grausenburger
a Children's Cancer Research Institute, St. Anna Kinderkrebsforschung , Vienna , Austria .
Stephan
S
Bastelberger
b Department of Pediatrics, Division of Oncology and Hematology , Charité, Berlin, Campus Virchow Klinikum , Berlin , Germany .
Cornelia
C
Eckert
a Children's Cancer Research Institute, St. Anna Kinderkrebsforschung , Vienna , Austria .
Maximilian
M
Kauer
c Department of Pediatrics , University Hospital Hannover , Hannover , Germany .
Martin
M
Stanulla
a Children's Cancer Research Institute, St. Anna Kinderkrebsforschung , Vienna , Austria .
Christian
C
Frech
d Ludwig Boltzmann Institute for Cancer Research , Vienna , Austria .
Eva
E
Bauer
d Ludwig Boltzmann Institute for Cancer Research , Vienna , Austria .|e Institute of Pharmacology, Medical University of Vienna , Vienna , Austria , and.
Dagmar
D
Stoiber
b Department of Pediatrics, Division of Oncology and Hematology , Charité, Berlin, Campus Virchow Klinikum , Berlin , Germany .
Arend
A
von Stackelberg
f St. Anna Kinderspital, Medical University Vienna , Vienna , Austria.
Andishe
A
Attarbaschi
a Children's Cancer Research Institute, St. Anna Kinderkrebsforschung , Vienna , Austria .|f St. Anna Kinderspital, Medical University Vienna , Vienna , Austria.
Oskar A
OA
Haas
a Children's Cancer Research Institute, St. Anna Kinderkrebsforschung , Vienna , Austria .
Renate
R
Panzer-Grümayer
D000818:Animals; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012008:Recurrence; D017384:Sequence Deletion; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D000097764:ETS Translocation Variant 6 Protein
D014408:Biomarkers, Tumor; D050676:Core Binding Factor Alpha 2 Subunit; D005938:Glucocorticoids; D015514:Oncogene Proteins, Fusion; D011965:Receptors, Glucocorticoid; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein
ALL relapses; ETV6/RUNX1; childhood ALL; genetic alterations; glucocorticoid signaling genes