Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
Department of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey.
PLoS One. 2020 Feb 27;15(2):e0229104. doi: 10.1371/journal.pone.0229104. eCollection 2020.
Tyrosine kinase inhibitor (TKI) resistance is a major problem in chronic myeloid leukemia (CML). We generated a TKI-resistant K562 sub-population, K562-IR, under selective imatinib-mesylate pressure. K562-IR cells are CD34-/CD38-, BCR-Abl-independent, proliferate slowly, highly adherent and form intact tumor spheroids. Loss of CD45 and other hematopoietic markers reveal these cells have diverged from their hematopoietic origin. CD34 negativity, high expression of E-cadherin and CD44; decreased levels of CD45 and β-catenin do not fully confer with the leukemic stem cell (LSC) phenotype. Expression analyses reveal that K562-IR cells differentially express tissue/organ development and differentiation genes. Our data suggest that the observed phenotypic shift is an adaptive process rendering cells under TKI stress to become oncogene independent. Cells develop transcriptional instability in search for a gene expression framework suitable for new environmental stresses, resulting in an adaptive phenotypic shift in which some cells partially display LSC-like properties. With leukemic/cancer stem cell targeted therapies underway, the difference between treating an entity and a spectrum of dynamic cellular states will have conclusive effects on the outcome.
酪氨酸激酶抑制剂 (TKI) 耐药是慢性髓细胞白血病 (CML) 的主要问题。我们在伊马替尼甲磺酸盐的选择性压力下产生了 TKI 耐药的 K562 亚群 K562-IR。K562-IR 细胞 CD34-/CD38-，BCR-Abl 独立，增殖缓慢，高度黏附，并形成完整的肿瘤球体。CD45 和其他造血标志物的缺失表明这些细胞已经与其造血起源分化。CD34 阴性、E-钙黏蛋白和 CD44 高表达；CD45 和 β-连环蛋白水平降低并不完全符合白血病干细胞 (LSC) 表型。表达分析显示 K562-IR 细胞差异表达组织/器官发育和分化基因。我们的数据表明，观察到的表型转变是一种适应性过程，使细胞在 TKI 压力下变得不依赖癌基因。细胞在寻找适合新环境压力的基因表达框架时会产生转录不稳定性，从而导致适应性表型转变，其中一些细胞部分显示出 LSC 样特性。随着针对白血病/癌症干细胞的靶向治疗的进行，在治疗实体和动态细胞状态谱之间的差异将对结果产生决定性影响。
