Transcriptional alterations in SKAP1-associated inside-out signaling in CNS-infiltrated pediatric T-cell acute lymphoblastic leukemia
4 affiliations
- 1Department of Women’s and Children’s Health, Division of Pediatric Oncology and Surgery, Karolinska Institutet, Stockholm, Sweden
- 2Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- 3Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
- 4Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA USA
Abstract
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 the molecular features associated with central nervous system (CNS) infiltration. Leukemia cells that migrate to the CNS can evade systemic therapy, contributing to disease progression and relapse. A better understanding of the transcriptomic profiles associated with CNS infiltration may provide insights into the underlying molecular programs involved in leukemic cell migration. Therefore, we aimed to identify transcriptional alterations that characterize CNS-infiltrated pediatric T-ALL patients. RNA-sequencing analysis revealed enrichment of genes associated with T-cell receptor (TCR) signaling, including SKAP1, a key adapter protein in the TCR-mediated inside-out signaling pathway, in both CNS-infiltrated and CNS-relapsed pediatric T-ALL. While inside-out signaling regulates normal T-cell adhesion and migration, its role in malignant leukemic cell migration remains unclear. In addition, T-ALL cells exposed to methotrexate and co-cultured with meningeal cells exhibited alterations in genes downstream of the TCR. Knockdown of SKAP1 resulted in reduced viability and proliferation of T-ALL cells. Collectively, these findings define a transcriptional profile associated with CNS infiltration in pediatric T-ALL, including altered TCR signaling and SKAP1 expression. Whether these alterations directly contribute to leukemic cell migration into the CNS remains to be established.
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BibTeX
@article{enlund2026transcriptional,
title = {{Transcriptional alterations in SKAP1-associated inside-out signaling in CNS-infiltrated pediatric T-cell acute lymphoblastic leukemia}},
author = {Sabina Enlund and Konstantinos Papadakis and Jacob Short and Ola Hermanson and Anna Nilsson and Qingfei Jiang and Frida Holm},
journal = {Cell Death Discovery},
year = {2026},
month = nov,
doi = {10.1038/s41420-026-03452-w},
url = {https://doi.org/10.1038/s41420-026-03452-w},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Transcriptional alterations in SKAP1-associated inside-out signaling in CNS-infiltrated pediatric T-cell acute lymphoblastic leukemia
AU - Sabina Enlund
AU - Konstantinos Papadakis
AU - Jacob Short
AU - Ola Hermanson
AU - Anna Nilsson
AU - Qingfei Jiang
AU - Frida Holm
PY - 2026
DA - 2026/11/05
JO - Cell Death Discovery
DO - 10.1038/s41420-026-03452-w
UR - https://doi.org/10.1038/s41420-026-03452-w
AB - 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 the molecular features associated with central nervous system (CNS) infiltration. Leukemia cells that migrate to the CNS can evade systemic therapy, contributing to disease progression and relapse. A better understanding of the transcriptomic profiles associated with CNS infiltration may provide insights into the underlying molecular programs involved in leukemic cell migration. Therefore, we aimed to identify transcriptional alterations that characterize CNS-infiltrated pediatric T-ALL patients. RNA-sequencing analysis revealed enrichment of genes associated with T-cell receptor (TCR) signaling, including SKAP1, a key adapter protein in the TCR-mediated inside-out signaling pathway, in both CNS-infiltrated and CNS-relapsed pediatric T-ALL. While inside-out signaling regulates normal T-cell adhesion and migration, its role in malignant leukemic cell migration remains unclear. In addition, T-ALL cells exposed to methotrexate and co-cultured with meningeal cells exhibited alterations in genes downstream of the TCR. Knockdown of SKAP1 resulted in reduced viability and proliferation of T-ALL cells. Collectively, these findings define a transcriptional profile associated with CNS infiltration in pediatric T-ALL, including altered TCR signaling and SKAP1 expression. Whether these alterations directly contribute to leukemic cell migration into the CNS remains to be established.
SN - 2058-7716
ER -