류아람 (The University of Texas at Austin, 현 University of California San Francisco) | 한빛사논문 > 한빛사

한빛사논문

조회631

류아람Aram Lyu

The University of Texas at Austin, 현 University of California San Francisco

Nat. Commun., Oct 07 2023, 14 (1) 6270 | https://doi.org/10.1038/s41467-023-41925-z Integrin signaling is critical for myeloid-mediated support of T-cell acute lymphoblastic leukemia.

Aram Lyu ^1,6, Ryan S. Humphrey ^1,6, Seo Hee Nam ¹, Tyler A. Durham ¹, Zicheng Hu ², Dhivya Arasappan ³, Terzah M. Horton ⁴ & Lauren I. R. Ehrlich ^1,5,*

¹Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA.
²Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA.
³Center for Biomedical Research Support, The University of Texas at Austin, Austin, TX, USA.
⁴Department of Pediatrics, Baylor College of Medicine/Dan L. Duncan Cancer Center and Texas Children’s Cancer Center, Houston, TX, USA.
⁵Department of Oncology, Livestrong Cancer Institutes, The University of Texas at Austin Dell Medical School, Austin, TX, USA.
⁶These authors contributed equally: Aram Lyu, Ryan S. Humphrey.

^*Corresponding author: correspondence to Lauren I. R. Ehrlich

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.

논문정보

형식Research article
게재일2023년 10월 (BRIC 등록일 2023-10-30)
연구진국외 연구진
분야 생명과학 > 면역학

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