Dysregulation of the inside-out signaling pathway in CNS-infiltrated pediatric T-cell acute lymphoblastic leukemia

A major obstacle to improving treatment efficacy and long-term survival in children with T-cell acute lymphoblastic leukemia (T-ALL) is the limited understanding of how leukemia cells infiltrate the central nervous system (CNS). By migrating to the CNS, leukemia cells can evade systemic therapy, contributing to disease progression and relapse. A better understanding of the mechanisms driving CNS infiltration in T-ALL could improve both diagnostic strategies and therapeutic interventions, thereby reducing the risk of CNS-originated relapse. One potential mechanism involves T-cell receptor (TCR)-mediated inside-out signaling, a pathway that regulates migration in normal T-cells and may be hijacked by leukemia cells invading the CNS. To investigate this possibility, we examined the role of this pathway in CNS-infiltrated pediatric T-ALL. RNA-sequencing analysis revealed enrichment of genes associated with the TCR signaling pathway, including adaptor protein SKAP1, a key component of inside-out signaling, in CNS-infiltrated and CNS-relapsed pediatric T-ALL samples. In addition, T-ALL cells exposed to methotrexate and co-cultured with meningeal cells exhibited alterations in signaling events downstream of the TCR. Knockdown of SKAP1 further resulted in reduced viability and proliferation of T-ALL cells. Collectively, these findings suggest that disruption of inside-out signaling may be characteristic for patients with CNS disease and could aid in providing new insights into the transcriptional programs underlying CNS infiltration in pediatric T-ALL.