Genetic alterations in glucocorticoid signaling pathway components are associated with adverse prognosis in children with relapsed ETV6/RUNX1-positive acute lymphoblastic leukemia

Abstract

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.

Keywords:

• ALL relapses
• childhood ALL
• ETV6/RUNX1
• genetic alterations
• glucocorticoid signaling genes

Acknowledgements

This work was financially supported by grants from the Austrian National Bank [ÖNB 14500] and Austrian Science Fund (FWF): [P 22073-B19]. The authors thank the St. Anna Kinderkrebsforschung for supporting the research of RP-G and Ludwig Boltzmann Institute for Cancer Research.

Potential conflict of interest

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Supplementary material available online