231 The role of the MR 7 Finally, we measured NR3C1 and NR3C2 mRNA expression in a cohort of 131 ALL patients with different ALL subtypes, including 28 ETV6-RUNX1 patients (Supplemental Table 1) and studied the association on early clinical response to seven days of prednisone and eventfree survival (EFS). Median NR3C1 expression in leukemic blasts (199.6 counts per million (CPM), range 41.9 to 567.1 CPM) was significantly higher than median NR3C2 expression (5.4 CPM, range 0.2 to 122.3 CPM). Only fourteen patients (11%) had a poor prednisone response, prohibiting both a univariable and multivariable regression analysis in this cohort to study a possible association between GR or MR expression and prednisone response (Supplemental Tables 1 and 2). One induction failure (0.8%), 22 relapses (16.8%) and two secondary malignancies (1.5%) were observed. In a univariable Cox regression, we did not find a significant association between high NR3C1 expression (hazard ratio (HR) 0.96, 95%-confidence interval (95%-CI) 0.40-2.30), nor high NR3C2 expression (HR 0.57, 95%-CI 0.24-1.33), and any event (Supplemental Table 4), suggesting that high expression of NR3C1 or NR3C2 does not predict for favorable outcome in our patient cohort. Kaplan-Meijer’s analysis also did not show an association between EFS and high or low NR3C1 or NR3C2 expression (Supplemental Figure 5). Together, these findings indicate that, even though a pronounced contribution of the MR exists in our models, the role of the MR in steroid-induced cytotoxicity is limited in ALL patients. Figure 3. NR3C2 expression in patients is relatively low (A), Relative expression of NR3C1 (blue) and NR3C2 (orange) in 279 primary ALL patient samples, dissected according to genetic background. (B), Cell toxicity screening of two primary patient samples and one PDX sample, all harboring the ETV6-RUNX1 fusion gene. Toxicity screening was performed using amino staining and data represents technical duplicates with standard deviations. Samples were treated with prednisolone, dexamethasone or hydrocortisone, in presence or absence of 4µM RU28318 (MR antagonist). ▶
RkJQdWJsaXNoZXIy MTk4NDMw