Abstract 3185: Integrin signaling is critical for myeloid-mediated support of T-ALL
| Autor: | Aram Lyu, Seo Hee Nam, Zicheng Hu, Lauren I.R. Ehrlich, Terzah M. Horton, Dhivya Arasappan |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Cancer Research. 81:3185-3185 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | T-cell acute lymphoblastic leukemia (T-ALL) is a malignant transformation of immature T cells. Although T-ALL harbors multiple pro-leukemic genetic alterations, T-ALL blasts require exogenous signals to survive. We recently reported that tumor-associated myeloid cells provide critical support for T-ALL in mouse models and in pediatric patient samples, at least partially through activation of IGF1R signaling. However, IGF1 alone is not sufficient to support T-ALL survival, implicating additional mechanisms in myeloid-mediated T-ALL support. We previously found that T-ALL cells make prolonged and frequent contacts with tumor-associated myeloid cells in live tissue sections; thus, we hypothesized that cell-cell interactions are essential for myeloid-mediated support of T-ALL. Here, we confirm that cell contact is required for myeloid cells to support T-ALL cell survival in vitro. Analysis of transcriptional profiling data revealed enrichment of gene signatures associated with integrin pathways in T-ALL cells relative to healthy T cells, implicating integrin-mediated cell adhesion as a potential mechanism underlying contact-dependent T-ALL support. Blockade of integrin αL ± integrin β1 or their ligands ICAM-1 ± VCAM-1 via antibodies or pharmacologic inhibitors significantly decreased T-ALL survival and reduced activation of IGF1R in T-ALL cells co-cultured with tumor-associated myeloid cells. Consistent with these findings, inhibition of integrins or their ligands in vivo via antibody blockade or genetic manipulation resulted in a significant reduction of T-ALL burden at multiple leukemic sites and prolonged survival. Consistent with mouse models, blockade of integrin-mediated cell adhesion significantly reduced survival of primary pediatric T-ALL cells co-cultured with myeloid cells. Furthermore, analyses of published transcriptomic datasets from pediatric T-ALL patients showed that enrichment of integrin pathways correlates with elevated myeloid gene signatures and poor patient prognosis. Together, our studies demonstrate that tumor-associated myeloid cells promote survival of T-ALL cells by activating integrin signaling, implicating the associated integrins and downstream signals as targets for therapeutic intervention. Citation Format: Aram Lyu, Seo Hee Nam, Zicheng Hu, Dhivya Arasappan, Terzah M. Horton, Lauren I. Ehrlich. Integrin signaling is critical for myeloid-mediated support of T-ALL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3185. |
| Databáze: | OpenAIRE |
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