Bibliographic Details
| Title: |
Integrin signaling is critical for myeloid-mediated support of T-cell acute lymphoblastic leukemia. |
| Authors: |
Lyu, Aram, Humphrey, Ryan S., Nam, Seo Hee, Durham, Tyler A., Hu, Zicheng, Arasappan, Dhivya, Horton, Terzah M., Ehrlich, Lauren I. R. |
| Source: |
Nature Communications; 10/7/2023, Vol. 14 Issue 1, p1-17, 17p |
| Subject Terms: |
LYMPHOBLASTIC leukemia, CELL adhesion, INSULIN receptors, ACUTE leukemia, FOCAL adhesion kinase, INTEGRINS, MYELOID cells, T cells, MYELOID differentiation factor 88 |
| 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. Tumor-associated myeloid cells directly support progression of T-cell acute lymphoblastic leukemia (TALL). Here, the authors show that T-ALL cells must contact myeloid cells and activate integrin signaling and downstream FAK/PYK2 kinases to survive. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
