ESPE Abstracts

Background: Synthetic glucocorticoid (GC) form crucial first-line treatment for childhood acute lymphoblastic leukemia (ALL). However, some patients reveal GC resistance with unknown mechanism. We have previously shown that reciprocal regulation of the GC metabolizing enzymes, 11beta-hydroxysteroid dehydrogenase types 1 and 2 (11b-HSD1 and 11b-HSD2) is associated with GC sensitivity/resistance in ALL at diagnosis. 11b-HSD1 predominantly regenerates active GC from inert 11-keto forms, whereas 11b-HSD2 inactivates GC.

Objective: The aim of this study was to investigate how 11b-HSD1/2 expression relates to clinical responsiveness following initial GC treatment in childhood ALL.

Methods: GC sensitive case 1 and resistant case 2 were investigated in this study. This study was approved by the Institutional Review Board. Bone marrow or peripheral blood samples were obtained during 7 days initial treatment with informed consent. GC sensitive case 1 was a 4-year-old girl who had relapsed B-cell precursor ALL. Case 2 was an 11-year-old boy with T-cell ALL, who showed GC resistance following 7 days prednisone treatment. Unfortunately, he died during induction therapy due to brain hemorrhage. in vitro GC sensitivity was determined by MTT assay. GC sensitive lymphoblastic leukemia CCRF-CEM and resistant MOLT4F cells were used for cell line experiments. mRNA levels were measured by qPCR.

Results: Case 1 was GC sensitive by MTT assay, whereas case 2 was initially GC sensitive at diagnosis but became resistant following 7 days prednisolone treatment. In case 1, an increase in 11b-HSD1 mRNA levels was associated with a decrease in leukemia cells during initial treatment including dexamethasone, whereas 11b-HSD2 mRNA levels were decreased and became undetectable following treatment. In case 2, 11b-HSD2 mRNA levels increased concomitantly with the increase in leukemia cells during prednisolone treatment, whereas 11b-HSD1 mRNA levels were undetectable. GC receptor mRNA levels following GC were also reduced following 7 days prednisolone treatment in case 2. Similar to patient samples, in GC sensitive CCRF-CEM cells, 11b-HSD1 mRNA levels were increased and 11b-HSD2 mRNA levels were decreased by dexamethasone. Increased 11b-HSD1/decreased 11b-HSD2 paralleled the degree of cell death. In GC resistant MOLT4F cells, dexamethasone induced cell death was improved by 11b-HSD2 knockdown by shRNA.

Conclusion: Increased 11b-HSD1 might be a useful biomarker of initial GC sensitivity, whereas increased 11b-HSD2 might associate with steroid resistance in childhood ALL. These findings may contribute to understand the mechanism of GC sensitivity/resistance in childhood ALL.