NR3C1 mutations, whether primary or acquired, may influence glucocorticoid (GC) resistance and treatment outcomes in pediatric patients with acute lymphoblastic leukemia (ALL), according to research published in Frontiers in Pharmacology.
Because of treatment advancements over the past several decades, pediatric ALL is curable in about 80% of cases. Disease relapse, however, remains a significant issue in about 20% of patients, and because of primary or acquired resistance, the prognosis among patients facing relapse is poor.
GCs are a mainstay of ALL treatment, and are used not only in ALL but other hematologic malignancies. Response to GCs is predictive of prognosis, and primary or evolved resistance to GCs is a significant predictor of disease relapse.
Previous work with next-generation sequencing suggests that a number of known genes – IKZF1, BTG1, TBL1XR1, CREBBP, and NR3C1 – are involved with GC resistance. NR3C1 mutations, in particular, are thought to have the strongest link with GC resistance, though the exact mechanisms are unknown.
For this study, researchers examined NR3C1 mutations in a cohort of pediatric patients with ALL, hypothesizing that a clearer understanding of the relationship between these mutations and GC resistance may aid in patient risk stratification, and, further, may lead to a new generation of novel ALL therapies.
Overall, between 2015 and 2020, a total of 351 patients with ALL were enrolled, among whom 333 had newly diagnosed and 18 had relapsed disease. NR3C1 mutations, specifically p. I539fs, p. P530fs, and p. H726P, were noted in 3 patients (0.9%) in the newly diagnosed group, while 2 patients (11.1%) in the relapsed disease group had such mutations (specifically, p. R477H and p. Y478C).
Analysis suggested that 4 of the 5 noted NR3C1 mutations – p. R477H, p. Y478C, p. P530fs, and p. H726P – were linked with loss of function, which was further linked with GC resistance.
“NR3C1 mutations are more frequent in ALL cases with relapse than in newly diagnosed cases,” the authors wrote. “In the future, deep sequencing to trace these acquired genetic mutations, permitting the early detection and treatment of relapse, may be warranted as another means to improve clinical outcomes.”
Liu H, Li Z, Qiu F, et al. Association between NR3C1 mutations and glucocorticoid resistance in children with acute lymphoblastic leukemia. Front Pharmacol. 2021;12:634956. doi:10.3389/fphar.2021.634956