Catholic High-Performance Cell Therapy Center and Department of Medical Life Science, College of Medicine, The Catholic University, Seoul.
Division of Hematology, Department of Internal Medicine, St Mary's Hematology Hospital, College of Medicine, The Catholic University of Korea.
Haematologica. 2022 Feb 1;107(2):381-392. doi: 10.3324/haematol.2020.269944.
Chemoresistance of leukemic cells has largely been attributed to clonal evolution secondary to accumulating mutations. Here, we show that a subset of leukemic blasts in contact with the mesenchymal stroma undergo cellular conversion into a distinct cell type that exhibits a stem cell-like phenotype and chemoresistance. These stroma-induced changes occur in a reversible and stochastic manner driven by cross-talk, whereby stromal contact induces interleukin-4 in leukemic cells that in turn targets the mesenchymal stroma to facilitate the development of new subset. This mechanism was dependent on interleukin-4-mediated upregulation of vascular cell adhesion molecule- 1 in mesenchymal stroma, causing tight adherence of leukemic cells to mesenchymal progenitors for generation of new subsets. Together, our study reveals another class of chemoresistance in leukemic blasts via functional evolution through stromal cross-talk, and demonstrates dynamic switching of leukemic cell fates that could cause a non-homologous response to chemotherapy in concert with the patient-specific microenvironment.
白血病细胞的化疗耐药性在很大程度上归因于积累突变导致的克隆进化。在这里，我们表明，与间充质基质接触的白血病细胞中的一部分亚群经历细胞转化为具有干细胞样表型和化疗耐药性的独特细胞类型。这些由基质诱导的变化以可逆和随机的方式发生，由细胞间通讯驱动，其中基质接触诱导白血病细胞中白细胞介素 4 的产生，进而靶向间充质基质以促进新亚群的发展。这种机制依赖于白细胞介素 4 介导的血管细胞黏附分子 1 在间充质基质中的上调，导致白血病细胞与间充质祖细胞紧密黏附，以产生新的亚群。总之，我们的研究通过基质细胞间通讯揭示了白血病细胞通过功能进化的另一种耐药机制，并证明了白血病细胞命运的动态转换，这可能导致与患者特定微环境协同的非同源性化疗反应。
