Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo-USP, Café Avenue, Ribeirão Preto, SP, Brazil.
Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo-USP, 3900 Bandeirantes Avenue, Ribeirão Preto, SP, Brazil.
Med Oncol. 2018 Jan 31;35(3):26. doi: 10.1007/s12032-018-1079-6.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm resulting from clonal expansion of hematopoietic stem cells positive for the Philadelphia chromosome. The CML pathogenesis is associated with expression of the BCR-ABL1 oncogene, which encodes the Bcr-Abl protein with tyrosine kinase activity, promoting the leukemic cell exacerbated myeloproliferation and resistance to apoptosis. CML patients are usually treated with tyrosine kinase inhibitors (TKI), but some of them acquire resistance or are refractory to TKI. Thus, it is still relevant to elucidate the CML pathogenesis and seek new therapeutic targets, such as the Hippo signaling pathway and cell cycle regulatory genes from the Aurora kinase family. The present study quantified the expression level of genes encoding components of the Hippo signaling pathway (LATS1, LATS2, YAP, and TAZ), AURKA and AURKB in CML patients at different stages of the disease, who were resistant or sensitive to imatinib mesylate therapy, and in healthy individuals. The expression levels of the target genes were correlated with the CML Sokal's prognostic score. The most striking results were the LATS2 and AURKA overexpression in CML patients, the overexpression of TAZ and AURKB in CML patients at advanced phases and TAZ in CML IM-resistant. The development of drugs and/or identification of tumor markers for the Hippo signaling pathway and the Aurora kinase family, either alone or in combination, can optimize CML treatment by enhancing the susceptibility of leukemic cells to apoptosis and leading to a better disease prognosis.
慢性髓系白血病（CML）是一种源于造血干细胞克隆性扩增的骨髓增殖性肿瘤，这些造血干细胞呈费城染色体阳性。CML 的发病机制与 BCR-ABL1 癌基因的表达有关，该基因编码具有酪氨酸激酶活性的 Bcr-Abl 蛋白，促进白血病细胞恶性增殖和抵抗凋亡。CML 患者通常采用酪氨酸激酶抑制剂（TKI）治疗，但其中一些患者会产生耐药性或对 TKI 治疗无效。因此，阐明 CML 的发病机制并寻找新的治疗靶点仍然具有重要意义，如 Hippo 信号通路和 Aurora 激酶家族的细胞周期调节基因。本研究定量检测了 Hippo 信号通路（LATS1、LATS2、YAP 和 TAZ）、AURKA 和 AURKB 编码组件在不同疾病阶段、对甲磺酸伊马替尼治疗耐药或敏感的 CML 患者以及健康个体中的表达水平。目标基因的表达水平与 CML Sokal 预后评分相关。最显著的结果是 LATS2 和 AURKA 在 CML 患者中的过度表达，TAZ 和 AURKB 在 CML 晚期患者中的过度表达，以及 CML IM 耐药患者中的 TAZ 过度表达。开发针对 Hippo 信号通路和 Aurora 激酶家族的药物和/或鉴定肿瘤标志物，无论是单独使用还是联合使用，都可以通过增强白血病细胞对凋亡的敏感性并改善疾病预后，从而优化 CML 的治疗。
