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. 2024 May 1;109(5):1551-1556.
doi: 10.3324/haematol.2023.282928.

The role of the mineralocorticoid receptor in steroidinduced cytotoxicity in pediatric acute lymphoblastic leukemia

Annelienke M Van Hulst  1 , Jordy C G Van der Zwet  2 , Jessica G C A M Buijs-Gladdines  2 , Willem K Smits  2 , Marta Fiocco  3 , Rob Pieters  2 , Frank N Van Leeuwen  2 , Marry M Van den Heuvel-Eibrink  4 , Erica L T Van den Akker  5 , Jules P P Meijerink  6
Affiliations

The role of the mineralocorticoid receptor in steroidinduced cytotoxicity in pediatric acute lymphoblastic leukemia

Annelienke M Van Hulst et al. Haematologica. .
No abstract available

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Figures

Figure 1.
Figure 1.
Hydrocortisone can induce expression of NR3C1 and NR3C2 via both the glucocorticoid receptor and the mineralocorticoid receptor. (A) Western blot analysis of DDK, NR3C1 and BIM in Reh cell lines that were transfected with either doxycycline-inducible DDK-tagged NR3C1 or NR3C2 constructs, after treatment with prednisone, dexamethasone or hydrocortisone, as indicated. (B) Transcriptional steroid response of Reh cell lines transfected with doxycycline-inducible NR3C1 or NR3C2 constructs. After doxycycline induction, cells were treated with 0.16 mM dexamethasone or 0.032 mM (RehNR3C1) or 0.0028 mM (RehNR3C2) hydrocortisone. Expression of NR3C1 (upper panels) and NR3C2 (lower panels) was measured in both cell lines, as was (C) the expression of BIM, GILZ and FKBP5, target genes of the glucocorticoid receptor and the mineralocorticoid receptor. Dox: doxycycline.
Figure 2.
Figure 2.
Hydrocortisone is the most potent steroid in NR3C1- and NR3C2-overexpressing cells. (A) Cell toxicity screening of RehNR3C1 (left) and RehNR3C2 (right) cells with (color) and without (gray-scales) doxycycline induction and after treatment with prednisolone, dexamethasone or hydrocortisone. Steroid sensitivity was determined with an MTT assay. Data represent biological triplicates, with standard deviations. (B) Cell toxicity screening of doxycycline-induced RehNR3C1 (upper panels) and RehNR3C2 (lower panels) with and without 4 mM RU28318 (mineralocorticoid receptor antagonist) treatment in combination with prednisolone, dexamethasone or hydrocortisone. RU28318 treatment in RehNR3C2 cells reversed the acquired steroid sensitivity. Dox: doxycycline; pred: prednisolone; dexa: dexamethasone; hydro: hydrocortisone; RU: RU28318.
Figure 3.
Figure 3.
NR3C2 expression in patients is relatively low. (A) Relative expression of NR3C1 (blue) and NR3C2 (orange) in 279 primary samples from patients with acute lymphoblastic leukemia, dissected according to genetic background. (B) Cell toxicity screening of two primary patients’ samples and one patient-derived xenograft sample, all harboring the ETV6-RUNX1 fusion gene. Toxicity screening was performed using amino staining and data represent technical duplicates with standard deviations. Samples were treated with prednisolone, dexamethasone or hydrocortisone, in the presence or absence of 4 mM RU28318 (a mineralocorticoid receptor antagonist). Area under the curve values were calculated using Prism software version 9.3.0 from GraphPad and statistically tested with a two-sided t test. iAMP21: intrachromosomal amplification of chromosome 21; NOS: not otherwise specified; T-ALL: T-cell acute lymphoblastic leukemia; PDX: patient-derived xenograft; AUC: area under the curve; pred: prednisolone; RU: RU28318; dexa: dexamethasone; hydro: hydrocortisone.
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References

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