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(Patho-)physiological activation of the IL7-receptor (IL7R) signaling contributes to steroid resistance in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Here, we show that activating IL7R pathway mutations and physiological IL7R signaling activate MAPK-ERK signaling, which provokes steroid resistance by phosphorylation of BIM. By mass spectrometry, we demonstrate that phosphorylated BIM is impaired in binding to BCL2, BCLXL and MCL1, shifting the apoptotic balance toward survival. Treatment with MEK inhibitors abolishes this inactivating phosphorylation of BIM and restores its interaction with anti-apoptotic BCL2-protein family members. Importantly, the MEK inhibitor selumetinib synergizes with steroids in both IL7-dependent and IL7-independent steroid resistant pediatric T-ALL PDX samples. Despite the anti-MAPK-ERK activity of ruxolitinib in IL7-induced signaling and JAK1 mutant cells, ruxolitinib only synergizes with steroid treatment in IL7-dependent steroid resistant PDX samples but not in IL7-independent steroid resistant PDX samples. Our study highlights the central role for MAPK-ERK signaling in steroid resistance in T-ALL patients, and demonstrates the broader application of MEK inhibitors over ruxolitinib to resensitize steroid-resistant T-ALL cells. These findings strongly support the enrollment of T-ALL patients in the current phase I/II SeluDex trial (NCT03705507) and contributes to the optimization and stratification of newly designed T-ALL treatment regimens., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

In the last decade, tremendous progress in curative treatment has been made for T-ALL patients using high-intensive, risk-adapted multi-agent chemotherapy. Further treatment intensification to improve the cure rate is not feasible as it will increase the number of toxic deaths. Hence, about 20% of pediatric patients relapse and often die due to acquired therapy resistance. Personalized medicine is of utmost importance to further increase cure rates and is achieved by targeting specific initiation, maintenance or resistance mechanisms of the disease. Genomic sequencing has revealed mutations that characterize genetic subtypes of many cancers including T-ALL. However, leukemia may have various activated pathways that are not accompanied by the presence of mutations. Therefore, screening for mutations alone is not sufficient to identify all molecular targets and leukemic dependencies for therapeutic inhibition. We review the extent of the driving type A and the secondary type B genomic mutations in pediatric T-ALL that may be targeted by specific inhibitors. Additionally, we review the need for additional screening methods on the transcriptional and protein levels. An integrated 'multi-omic' screening will identify potential targets and biomarkers to establish significant progress in future individualized treatment of T-ALL patients., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)