Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-8655, Japan.
Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-8655, Japan.
Stem Cell Reports. 2018 Mar 13;10(3):1115-1130. doi: 10.1016/j.stemcr.2018.01.015. Epub 2018 Feb 8.
Properties of cancer stem cells involved in drug resistance and relapse have significant effects on clinical outcome. Although tyrosine kinase inhibitors (TKIs) have dramatically improved survival of patients with chronic myeloid leukemia (CML), TKIs have not fully cured CML due to TKI-resistant CML stem cells. Moreover, relapse after discontinuation of TKIs has not been predicted in CML patients with the best TKI response. In our study, a model of CML stem cells derived from CML induced pluripotent stem cells identified ADAM8 as an antigen of TKI-resistant CML cells. The inhibition of expression or metalloproteinase activity of ADAM8 restored TKI sensitivity in primary samples. In addition, residual CML cells in patients with optimal TKI response were concentrated in the ADAM8+ population. Our study demonstrates that ADAM8 is a marker of residual CML cells even in patients with optimal TKI response and would be a predictor of relapse and a therapeutic target of TKI-resistant CML cells.
癌症干细胞的耐药性和复发相关特性对临床结果有重要影响。虽然酪氨酸激酶抑制剂（TKI）显著改善了慢性髓细胞白血病（CML）患者的生存，但由于 TKI 耐药的 CML 干细胞，TKI 并未完全治愈 CML。此外，TKI 反应最佳的 CML 患者停止 TKI 后复发并未得到预测。在我们的研究中，从 CML 诱导多能干细胞中鉴定出 ADAM8 作为 TKI 耐药 CML 细胞的抗原，CML 干细胞模型。抑制 ADAM8 的表达或金属蛋白酶活性可恢复原代样本中 TKI 的敏感性。此外，最佳 TKI 反应患者中的残留 CML 细胞集中在 ADAM8+群体中。我们的研究表明，ADAM8 是残留 CML 细胞的标志物，即使在 TKI 反应最佳的患者中也是如此，它将成为复发的预测因子和 TKI 耐药的 CML 细胞的治疗靶点。
