Lyu Aram, Humphrey Ryan S, Nam Seo Hee, Durham Tyler A, Hu Zicheng, Arasappan Dhivya, Horton Terzah M, Ehrlich Lauren I R
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA.
Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA.
Nat Commun. 2023 Oct 7;14(1):6270. doi: 10.1038/s41467-023-41925-z.
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.
我们之前发现，T细胞急性淋巴细胞白血病（T-ALL）需要肿瘤相关髓样细胞的支持，这些髓样细胞可激活白血病母细胞中的胰岛素样生长因子1受体（IGF1R）信号通路。然而，IGF1在体外不足以维持T-ALL，这表明白血病进展中还存在其他髓样细胞介导的信号。在此，我们发现T-ALL细胞需要与髓样细胞紧密接触才能存活。转录谱分析和体外实验表明，整合素介导的细胞黏附可激活下游黏着斑激酶（FAK）/富含脯氨酸的酪氨酸激酶2（PYK2），这是髓样细胞介导的T-ALL支持所必需的，部分是通过激活IGF1R实现的。阻断整合素配体或抑制FAK/PYK2信号通路可减轻多个器官的白血病负担，并在T-ALL小鼠模型中赋予生存优势。抑制整合素介导的黏附或FAK/PYK2也会降低与髓样细胞共培养的原发性患者T-ALL细胞的存活率。此外，整合素通路基因特征的升高与更高的FAK信号和髓样基因特征相关，并与儿童T-ALL患者的预后较差有关。总之，这些发现表明整合素激活和下游FAK/PYK2信号通路是髓样细胞介导的T-ALL进展支持的重要机制。
