Language
English
Publication Date
10-7-2023
Journal
Nature Communications
DOI
10.1038/s41467-023-41925-z
PMID
37805579
PMCID
PMC10560206
PubMedCentral® Posted Date
10-7-2023
PubMedCentral® Full Text Version
Post-print
Abstract
We previously found that T-cell acute lymphoblastic leukemia (T-ALL) requires support from tumor-associated myeloid cells, which activate Insulin Like Growth Factor 1 Receptor (IGF1R) signaling in leukemic blasts. However, IGF1 is not sufficient to sustain T-ALL in vitro, implicating additional myeloid-mediated signals in leukemia progression. Here, we find that T-ALL cells require close contact with myeloid cells to survive. Transcriptional profiling and in vitro assays demonstrate that integrin-mediated cell adhesion activates downstream focal adhesion kinase (FAK)/ proline-rich tyrosine kinase 2 (PYK2), which are required for myeloid-mediated T-ALL support, partly through activation of IGF1R. Blocking integrin ligands or inhibiting FAK/PYK2 signaling diminishes leukemia burden in multiple organs and confers a survival advantage in a mouse model of T-ALL. Inhibiting integrin-mediated adhesion or FAK/PYK2 also reduces survival of primary patient T-ALL cells co-cultured with myeloid cells. Furthermore, elevated integrin pathway gene signatures correlate with higher FAK signaling and myeloid gene signatures and are associated with an inferior prognosis in pediatric T-ALL patients. Together, these findings demonstrate that integrin activation and downstream FAK/PYK2 signaling are important mechanisms underlying myeloid-mediated support of T-ALL progression.
Keywords
Mice, Animals, Humans, Child, Focal Adhesion Kinase 2, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Signal Transduction, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Integrins, T-Lymphocytes, Phosphorylation, Acute lymphocytic leukaemia, Cancer microenvironment
Published Open-Access
yes
Recommended Citation
Lyu, Aram; Humphrey, Ryan S; Nam, Seo Hee; et al., "Integrin Signaling Is Critical for Myeloid-Mediated Support of T-Cell Acute Lymphoblastic Leukemia" (2023). Faculty, Staff and Students Publications. 8075.
https://digitalcommons.library.tmc.edu/baylor_docs/8075