Horm Metab Res
DOI: 10.1055/a-2363-4823
Original Article: Endocrine Care

Glucocorticoid Sensitivity Among Young Survivors of Childhood Acute Lymphoblastic Leukemia: What Does It Matter?

1   Pediatric Endocrinology, Federal University of Sao Paulo – UNIFESP/EPM, Sao Paulo, Brazil
2   Pediatric Endocrinology, Hospital of the Support Group for Adolescent and Children with Cancer – GRAACC, Sao Paulo, Brazil
,
AnaVirgínia Lopes de Sousa
3   Pediatric Oncology, Hospital of the Support Group for Adolescent and Children with Cancer – GRAACC, Sao Paulo, Brazil
,
Bruno Moreira Simião
1   Pediatric Endocrinology, Federal University of Sao Paulo – UNIFESP/EPM, Sao Paulo, Brazil
,
Elisangela Oliveira Araújo
4   Physiological Sciences, Faculty of Medical Sciences of Santa Casa de Sao Paulo – FCM SCSP, Sao Paulo, Brazil
,
Renato Alvarenga
4   Physiological Sciences, Faculty of Medical Sciences of Santa Casa de Sao Paulo – FCM SCSP, Sao Paulo, Brazil
,
1   Pediatric Endocrinology, Federal University of Sao Paulo – UNIFESP/EPM, Sao Paulo, Brazil
2   Pediatric Endocrinology, Hospital of the Support Group for Adolescent and Children with Cancer – GRAACC, Sao Paulo, Brazil
,
4   Physiological Sciences, Faculty of Medical Sciences of Santa Casa de Sao Paulo – FCM SCSP, Sao Paulo, Brazil
› Author Affiliations
Supported by: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) 18/21342-0 to AAS-M

Abstract

The aim of the study was to assess glucocorticoid sensitivity in survivors of childhood acute lymphoblastic leukemia using in vivo and in vitro tests. Thirty leukemia survivors of both sexes aged ≥18 years participated in the study and at least two years after therapy withdrawal. In vivo tests comprised: a) a very low dose intravenous dexamethasone suppression test for measurement of serum cortisol before, after, and % suppression, compared with 32 age-matched controls; and b) 0.25 mg overnight oral dexamethasone suppression test for assessment of salivary cortisol before, after, and % suppression. In vitro methods comprised: c) glucocorticoid receptor polymorphisms: BcI1-NR3C1 and A3669G; and d) splicing variant of glucocorticoid receptor GR-α mRNA by real-time quantitative polymerase chain reaction, compared with 32 controls. There was a reduction in salivary cortisol, and 73.3% of leukemia survivors showed high sensitivity according to % suppression after oral dexamethasone (p<0.05). Serum cortisol at baseline, after the test, % suppression after intravenous dexamethasone, and the percentage of high sensitivity were reduced in the leukemia group (%F=36.7; p<0.05). The BcI1-NR3C1 and A3669G polymorphisms were present in 11/30 (36.7%) and 5/30 (16.7%) patients, respectively. GR-α mRNA levels were lower in the leukemia group than in the controls (p<0.05). Survivors of acute lymphoblastic leukemia presented with reduced glucocorticoid sensitivity. Glucocorticoid sensitivity allows individualized treatment to avoid adverse effects and may be involved in cardiovascular disease risk among this particular group of cancer survivors.



Publication History

Received: 22 October 2023

Accepted after revision: 01 July 2024

Article published online:
05 August 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Longui CA, Faria CD. Evaluation of glucocorticoid sensitivity and its potential clinical applicability. Horm Res 2009; 71: 305-309
  • 2 Quax RA, Manenschijn L, Koper JW. et al. Glucocorticoid sensitivity in health and disease. Nat Rev Endocrinol 2013; 9: 670-686
  • 3 Gross KL, Lu NZ, Cidlowski JA. Molecular mechanisms regulating glucocorticoid sensitivity and resistance. Mol Cell Endocrinol 2009; 300: 7-16
  • 4 Ramamoorthy S, Cidlowski JA. Corticosteroids: mechanisms of action in health and disease. Rheum Dis Clin North Am 2016; 42: 15-31
  • 5 Sevilla LM, Jiménez-Panizo A, Alegre-Martí A. et al. Glucocorticoid resistance: interference between the glucocorticoid receptor and the MAPK Signalling pathways. Int J Mol Sci 2021; 22: 10049
  • 6 Bhadri VA, Trahair TN, Lock RB. Glucocorticoid resistance in paediatric acute lymphoblastic leukaemia. J Paediatr Child Health 2012; 48: 634-640
  • 7 Olivas-Aguirre M, Torres-López L, Pottosin I. et al. Overcoming glucocorticoid resistance in acute lymphoblastic leukemia: repurposed drugs can improve the protocol. Front Oncol 2021; 11: 617937
  • 8 Zhang Z, Shi J, Wu Q. et al. JUN mediates glucocorticoid resistance by stabilizing HIF1a in T cell acute lymphoblastic leukemia. iScience 2023; 26: 108242
  • 9 Eipel O, Hegyi M, Csordás K. et al. Some GCR polymorphisms (N363S, ER22/23EK, and Bcl-1) may influence steroid-induced toxicities and survival rates in children with ALL. J Pediatr Hematol Oncol 2016; 38: 334-340
  • 10 Kaymak Cihan M, Karabulut HG, Yürür Kutlay N. et al. Association between N363S and BclI polymorphisms of the glucocorticoid receptor gene (NR3C1) and glucocorticoid side effects during childhood acute lymphoblastic leukemia treatment. Turk J Haematol 2017; 34: 151-158
  • 11 Tamai M, Kasai S, Akahane K. et al. Glucocorticoid receptor gene mutations confer glucocorticoid resistance in B-cell precursor acute lymphoblastic leukemia. J Steroid Biochem Mol Biol 2022; 218: 106068
  • 12 El-Fayoumi R, Hagras M, Abozenadaha A. et al. Association between NR3C1 Gene polymorphisms and toxicity induced by glucocorticoids therapy in Saudi children with acute lymphoblastic leukemia. Asian Pac J Cancer Prev 2018; 19: 1415-1423
  • 13 ElFayoumi RI, Hagras MM, Abozenadaha A. et al. The influence of polymorphisms in the drug transporter, ABCB1 on the toxicity of glucocorticoids in Saudi children with acute lymphoblastic leukaemia. Pharmacol Rep 2019; 71: 90-95
  • 14 Longui CA, Vottero A, Adamson PC. et al. Low glucocorticoid receptor alpha/beta ratio in T-cell lymphoblastic leukemia. Horm Metab Res 2000; 32: 401-406
  • 15 Haarman EG, Kaspers GJ, Pieters R. et al. Glucocorticoid receptor alpha, beta and gamma expression vs in vitro glucocorticod resistance in childhood leukemia. Leukemia 2004; 18: 530-537
  • 16 Koga Y, Matsuzaki A, Suminoe A. et al. Differential mRNA expression of glucocorticoid receptor alpha and beta is associated with glucocorticoid sensitivity of acute lymphoblastic leukemia in children. Pediatr Blood Cancer 2005; 45: 121-127
  • 17 Tissing WJ, Meijerink JP, den Boer ML. et al. mRNA expression levels of (co)chaperone molecules of the glucocorticoid receptor are not involved in glucocorticoid resistance in pediatric ALL. Leukemia 2005; 19: 727-733
  • 18 Sun X, Fang M, Guan Y. et al. Changes of glucocorticoid receptor isoforms expression in acute lymphoblastic leukemia correlate with glucocorticoid resistance. Pharmazie 2015; 70: 316-321
  • 19 Hall CP, Reynolds CP, Kang MH. Modulation of glucocorticoid resistance in pediatric T-cell acute lymphoblastic leukemia by increasing BIM expression with the PI3K/mTOR inhibitor BEZ235. Clin Cancer Res 2016; 22: 621-632
  • 20 Zimmerman JAO, Fang M, Pufall MA. PI3Kδ Inhibition potentiates glucocorticoids in B-lymphoblastic leukemia by decreasing receptor phosphorylation and enhancing gene regulation. Cancers (Basel) 2023; 16: 143
  • 21 Bride KL, Hu H, Tikhonova A. et al. Rational drug combinations with CDK4/6 inhibitors in acute lymphoblastic leukemia. Haematologica 2022; 107: 1746-1757
  • 22 Gezelius H, Enblad AP, Lundmark A. et al. Comparison of high-throughput single-cell RNA-seq methods for ex vivo drug screening. NAR Genom Bioinform 2024; 6: lqae001
  • 23 Willemsen RH, van Leeuwen L, Voorend-van Bergen TA. et al. Reproducibility and utility of an overnight 0.25 mg dexamethasone suppression test as a marker for glucocorticoid sensitivity in children with asthma. J Endocrinol Invest 2016; 39: 93-96
  • 24 Diaz-Marsa M, Carrasco JL, Basurte E. et al. Findings with 0.25 mg dexamethasone suppression test in eating disorders: association with childhood trauma. CNS Spectr 2007; 12: 675-680
  • 25 Faria CD, Cobra JF, Sousa E, Silva T. et al. A very low dose intravenous dexamethasone suppression test as an index of glucocorticoid sensitivity. Horm Res 2008; 69: 357-362
  • 26 Cobra JF, Melo MR, Faria CD. et al. Simultaneous evaluation of in vivo glucocorticoid sensitivity and expression of glucocorticoid receptor alpha-isoform in rheumatoid arthritis patients. Arq Bras Endocrinol Metabol 2009; 53: 24-30
  • 27 Cavalcante LO, Melo MR, Dinis VG. et al. Quantitation of glucocorticoid receptor alpha and NF-κB pathway mRNA and its correlation with disease activity in rheumatoid arthritis patients. Genet Mol Res 2010; 9: 2300-2310
  • 28 Melo AK, Melo MR, Saramago AB. et al. Persistent glucocorticoid resistance in systemic lupus erythematosus patients during clinical remission. Genet Mol Res 2013; 12: 2010-2019
  • 29 Martins CS, Elias D, Colli LM. et al HPA axis dysregulation, NR3C1 polymorphisms and glucocorticoid receptor isoforms imbalance in metabolic syndrome. Diabetes Metab Res Rev. 2017; 33 DOI: 10.1002/dmrr.2842. Epub 2016 Oct 24
  • 30 Kolb KL, Mira ALS, Auer ED. et al. Glucocorticoid Receptor Gene (NR3C1) polymorphisms and metabolic syndrome: insights from the Mennonite Population. Genes (Basel) 2023; 14: 1805
  • 31 Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969; 44: 291-303
  • 32 Marshall WA, Tanner JM. Variations in pattern of pubertal changes in boys. Arch Dis Child 1970; 45: 13-23
  • 33 Moreira RP, Gomes LG, Madureira G. et al. Influence of the A3669G glucocorticoid receptor gene polymorphism on the metabolic profile of pediatric patients with congenital adrenal hyperplasia. Int J Endocrinol. 2014 594710.
  • 34 Melo MR, Faria CD, Melo KC. et al. Real-time PCR quantitation of glucocorticoid receptor alpha isoform. BMC Mol Biol 2004; 5: 19
  • 35 Vieira JG, Nakamura OH, Carvalho VM. Determination of cortisol and cortisone in human saliva by a liquid chromatography-tandem mass spectrometry method. Arq Bras Endocrinol Metabol 2014; 58: 844-850
  • 36 McWhinney BC, Briscoe SE, Ungerer JPJ. et al. Measurement of cortisol, cortisone, prednisolone, dexamethasone and 11-deoxycortisol with ultra high performance liquid chromatography-tandem mass spectrometry: Application for plasma, plasma ultrafiltrate, urine and saliva in a routine laboratory. J Chromatogr B Analyt Technol Biomed Life Sci 2010; 878: 2863-2869
  • 37 Trementino L, Appolloni G, Concettoni C. et al. Association of glucocorticoid receptor polymorphism A3669G with decreased risk of developing diabetes in patients with Cushing's syndrome. Eur J Endocrinol 2012; 166: 35-42
  • 38 Moreira RP, Bachega TA, Machado MC. et al. Modulatory effect of BclI GR gene polymorphisms on the obesity phenotype in Brazilian patients with Cushing's disease. Clinics (Sao Paulo) 2013; 68: 579-585
  • 39 Souza MC, Martins CS, Silva-Junior IM. et al. NR3C1 polymorphisms in Brazilians of Caucasian, African, and Asian ancestry: glucocorticoid sensitivity and genotype association. Arq Bras Endocrinol Metabol 2014; 58: 53-61
  • 40 Siviero-Miachon AA, Spinola-Castro AM, Guerra-Junior G. Detection of metabolic syndrome features among childhood cancer survivors: a target to prevent disease. Vasc Health Risk Manag 2008; 4: 825-836
  • 41 Nottage KA, Ness KK, Li C. et al. Metabolic syndrome and cardiovascular risk among long-term survivors of acute lymphoblastic leukaemia – From the St. Jude Lifetime Cohort. Br J Haematol 2014; 165: 364-374